Anti-viral compounds

ABSTRACT

The present invention features compounds effective in inhibiting active against Hepatitis C virus (“HCV”) polymerase. The invention also features processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/254,342, filed Sep. 1, 2016, now U.S. Pat. No. 9,676,797, issued Jun.13, 2017. The contents of which are incorporated herein by reference.This application also claims the benefit of priority to U.S. ProvisionalApplication No. 62/213,378, filed Sep. 2, 2015, U.S. ProvisionalApplication No. 62/242,136, filed Oct. 15, 2015, U.S. ProvisionalApplication No. 62/253,426, filed Nov. 10, 2015, U.S. ProvisionalApplication No. 62/294,449, filed Feb. 12, 2016, U.S. ProvisionalApplication No. 62/296,801, filed Feb. 18, 2016, U.S. ProvisionalApplication No. 62/321,538, filed Apr. 12, 2016, U.S. ProvisionalApplication No. 62/327,087, filed Apr. 25, 2016, U.S. ProvisionalApplication No. 62/351,038, filed Jun. 16, 2016, U.S. ProvisionalApplication No. 62/363,640, filed Jul. 18, 2016 and U.S. ProvisionalApplication No. 62/375,029, filed Aug. 15, 2016. The contents of eachapplication are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds effective in inhibitingreplication of Hepatitis C virus (“HCV”). The present invention alsorelates to compositions comprising these compounds and methods of usingthese compounds to treat HCV infection.

BACKGROUND OF THE INVENTION

The HCV is an RNA virus belonging to the Hepacivirus genus in theFlaviviridae family. The enveloped HCV virion contains a positivestranded RNA genome encoding all known virus-specific proteins in asingle, uninterrupted, open reading frame. The open reading framecomprises approximately 9500 nucleotides and encodes a single largepolyprotein of about 3000 amino acids. The polyprotein comprises a coreprotein, envelope proteins E1 and E2, a membrane bound protein p7, andthe non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

Chronic HCV infection is associated with progressive liver pathology,including cirrhosis and hepatocellular carcinoma. Chronic hepatitis Cmay be treated with peginterferon-alpha in combination with ribavirin.Substantial limitations to efficacy and tolerability remain as manyusers suffer from side effects, and viral elimination from the body isoften incomplete. Therefore, there is a need for new therapies to treatHCV infection.

DETAILED DESCRIPTION

In one aspect, the present invention features compounds having FormulaI, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula I, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1:

TABLE 1 Compound No. X R₁ R₂ R₃ R₄ R₅ 1 O F Cl OH H N₃ 2 O F Cl OH HOCH₃ 3 O F Cl OH H CN 4 O F Cl OH H 1H-imidazol-1-yl 5 O F Cl OH H1H-imidazol-2-yl 6 O F Cl OH H 1H-imidazol-5-yl 7 O F Cl OH H1H-tetrazol-1-yl 8 O F Cl OH H 2H-tetrazol-2-yl 9 O F Cl OH H1H-tetrazol-5-yl 10 O F Br OH H H 11 O F Br OH H D 12 O F Br OH H F 13 OF Br OH H N₃ 14 O F Br OH H OCH₃ 15 O F Br OH H CN 16 O F Br OH H1H-imidazol-1-yl 17 O F Br OH H 1H-imidazol-2-yl 18 O F Br OH H1H-imidazol-5-yl 19 O F Br OH H 1H-tetrazol-1-yl 20 O F Br OH H2H-tetrazol-2-yl 21 O F Br OH H 1H-tetrazol-5-yl 22 O Cl F OH H N₃ 23 OCl F OH H OCH₃ 24 O Cl F OH H CN 25 O Cl F OH H 1H-imidazol-1-yl 26 O ClF OH H 1H-imidazol-2-yl 27 O Cl F OH H 1H-imidazol-5-yl 28 O Cl F OH H1H-tetrazol-1-yl 29 O Cl F OH H 2H-tetrazol-2-yl 30 O Cl F OH H1H-tetrazol-5-yl 31 O Cl Cl OH H N₃ 32 O Cl Cl OH H OCH₃ 33 O Cl Cl OH HCN 34 O Cl Cl OH H 1H-imidazol-1-yl 35 O Cl Cl OH H 1H-imidazol-2-yl 36O Cl Cl OH H 1H-imidazol-5-yl 37 O Cl Cl OH H 1H-tetrazol-1-yl 38 O ClCl OH H 2H-tetrazol-2-yl 39 O Cl Cl OH H 1H-tetrazol-5-yl 40 O Cl Br OHH H 41 O Cl Br OH H D 42 O Cl Br OH H F 43 O Cl Br OH H N₃ 44 O Cl Br OHH OCH₃ 45 O Cl Br OH H CN 46 O Cl Br OH H 1H-imidazol-1-yl 47 O Cl Br OHH 1H-imidazol-2-yl 48 O Cl Br OH H 1H-imidazol-5-yl 49 O Cl Br OH H1H-tetrazol-1-yl 50 O Cl Br OH H 2H-tetrazol-2-yl 51 O Cl Br OH H1H-tetrazol-5-yl 52 O Br F OH H H 53 O Br F OH H D 54 O Br F OH H F 55 OBr F OH H N₃ 56 O Br F OH H OCH₃ 57 O Br F OH H CN 58 O Br F OH H1H-imidazol-1-yl 59 O Br F OH H 1H-imidazol-2-yl 60 O Br F OH H1H-imidazol-5-yl 61 O Br F OH H 1H-tetrazol-1-yl 62 O Br F OH H2H-tetrazol-2-yl 63 O Br F OH H 1H-tetrazol-5-yl 64 O Br Cl OH H H 65 OBr Cl OH H D 66 O Br Cl OH H F 67 O Br Cl OH H N₃ 68 O Br Cl OH H OCH₃69 O Br Cl OH H CN 70 O Br Cl OH H 1H-imidazol-1-yl 71 O Br Cl OH H1H-imidazol-2-yl 72 O Br Cl OH H 1H-imidazol-5-yl 73 O Br Cl OH H1H-tetrazol-1-yl 74 O Br Cl OH H 2H-tetrazol-2-yl 75 O Br Cl OH H1H-tetrazol-5-yl 76 O Br Br OH H H 77 O Br Br OH H D 78 O Br Br OH H F79 O Br Br OH H N₃ 80 O Br Br OH H OCH₃ 81 O Br Br OH H CN 82 O Br Br OHH 1H-imidazol-1-yl 83 O Br Br OH H 1H-imidazol-2-yl 84 O Br Br OH H1H-imidazol-5-yl 85 O Br Br OH H 1H-tetrazol-1-yl 86 O Br Br OH H2H-tetrazol-2-yl 87 O Br Br OH H 1H-tetrazol-5-yl 88 O CH₃ CH₃ OH H H 89O CH₃ CH₃ OH H D 90 O CH₃ CH₃ OH H F 91 O CH₃ CH₃ OH H N₃ 92 O CH₃ CH₃OH H OCH₃ 93 O CH₃ CH₃ OH H CN 94 O CH₃ CH₃ OH H 1H-imidazol-1-yl 95 OCH₃ CH₃ OH H 1H-imidazol-2-yl 96 O CH₃ CH₃ OH H 1H-imidazol-5-yl 97 OCH₃ CH₃ OH H 1H-tetrazol-1-yl 98 O CH₃ CH₃ OH H 2H-tetrazol-2-yl 99 OCH₃ CH₃ OH H 1H-tetrazol-5-yl 100 O CH₃ CCH OH H N₃ 101 O CH₃ CCH OH HOCH₃ 102 O CH₃ CCH OH H CN 103 O CH₃ CCH OH H 1H-imidazol-1-yl 104 O CH₃CCH OH H 1H-imidazol-2-yl 105 O CH₃ CCH OH H 1H-imidazol-5-yl 106 O CH₃CCH OH H 1H-tetrazol-1-yl 107 O CH₃ CCH OH H 2H-tetrazol-2-yl 108 O CH₃CCH OH H 1H-tetrazol-5-yl 109 O F CCH OH H N₃ 110 O F CCH OH H OCH₃ 111O F CCH OH H CN 112 O F CCH OH H 1H-imidazol-1-yl 113 O F CCH OH H1H-imidazol-2-yl 114 O F CCH OH H 1H-imidazol-5-yl 115 O F CCH OH H1H-tetrazol-1-yl 116 O F CCH OH H 2H-tetrazol-2-yl 117 O F CCH OH H1H-tetrazol-5-yl 118 O Cl CCH OH H H 119 O Cl CCH OH H D 120 O Cl CCH OHH F 121 O Cl CCH OH H N₃ 122 O Cl CCH OH H OCH₃ 123 O Cl CCH OH H CN 124O Cl CCH OH H 1H-imidazol-1-yl 125 O Cl CCH OH H 1H-imidazol-2-yl 126 OCl CCH OH H 1H-imidazol-5-yl 127 O Cl CCH OH H 1H-tetrazol-1-yl 128 O ClCCH OH H 2H-tetrazol-2-yl 129 O Cl CCH OH H 1H-tetrazol-5-yl 130 O BrCCH OH H H 131 O Br CCH OH H D 132 O Br CCH OH H F 133 O Br CCH OH H N₃134 O Br CCH OH H OCH₃ 135 O Br CCH OH H CN 136 O Br CCH OH H1H-imidazol-1-yl 137 O Br CCH OH H 1H-imidazol-2-yl 138 O Br CCH OH H1H-imidazol-5-yl 139 O Br CCH OH H 1H-tetrazol-1-yl 140 O Br CCH OH H2H-tetrazol-2-yl 141 O Br CCH OH H 1H-tetrazol-5-yl 142 O CHF₂ CCH OH HH 143 O CHF₂ CCH OH H D 144 O CHF₂ CCH OH H F 145 O CHF₂ CCH OH H N₃ 146O CHF₂ CCH OH H OCH₃ 147 O CHF₂ CCH OH H CN 148 O CHF₂ CCH OH H1H-imidazol-1-yl 149 O CHF₂ CCH OH H 1H-imidazol-2-yl 150 O CHF₂ CCH OHH 1H-imidazol-5-yl 151 O CHF₂ CCH OH H 1H-tetrazol-1-yl 152 O CHF₂ CCHOH H 2H-tetrazol-2-yl 153 O CHF₂ CCH OH H 1H-tetrazol-5-yl 154 O CH₂FCCH OH H H 155 O CH₂F CCH OH H D 156 O CH₂F CCH OH H F 157 O CH₂F CCH OHH N₃ 158 O CH₂F CCH OH H OCH₃ 159 O CH₂F CCH OH H CN 160 O CH₂F CCH OH H1H-imidazol-1-yl 161 O CH₂F CCH OH H 1H-imidazol-2-yl 162 O CH₂F CCH OHH 1H-imidazol-5-yl 163 O CH₂F CCH OH H 1H-tetrazol-1-yl 164 O CH₂F CCHOH H 2H-tetrazol-2-yl 165 O CH₂F CCH OH H 1H-tetrazol-5-yl 166 C═CH₂ FCl OH H N₃ 167 C═CH₂ F Cl OH H OCH₃ 168 C═CH₂ F Cl OH H CN 169 C═CH₂ FCl OH H 1H-imidazol-1-yl 170 C═CH₂ F Cl OH H 1H-imidazol-2-yl 171 C═CH₂F Cl OH H 1H-imidazol-5-yl 172 C═CH₂ F Cl OH H 1H-tetrazol-1-yl 173C═CH₂ F Cl OH H 2H-tetrazol-2-yl 174 C═CH₂ F Cl OH H 1H-tetrazol-5-yl175 C═CH₂ F Br OH H H 176 C═CH₂ F Br OH H D 177 C═CH₂ F Br OH H F 178C═CH₂ F Br OH H N₃ 179 C═CH₂ F Br OH H OCH₃ 180 C═CH₂ F Br OH H CN 181C═CH₂ F Br OH H 1H-imidazol-1-yl 182 C═CH₂ F Br OH H 1H-imidazol-2-yl183 C═CH₂ F Br OH H 1H-imidazol-5-yl 184 C═CH₂ F Br OH H1H-tetrazol-1-yl 185 C═CH₂ F Br OH H 2H-tetrazol-2-yl 186 C═CH₂ F Br OHH 1H-tetrazol-5-yl 187 C═CH₂ Cl F OH H N₃ 188 C═CH₂ Cl F OH H OCH₃ 189C═CH₂ Cl F OH H CN 190 C═CH₂ Cl F OH H 1H-imidazol-1-yl 191 C═CH₂ Cl FOH H 1H-imidazol-2-yl 192 C═CH₂ Cl F OH H 1H-imidazol-5-yl 193 C═CH₂ ClF OH H 1H-tetrazol-1-yl 194 C═CH₂ Cl F OH H 2H-tetrazol-2-yl 195 C═CH₂Cl F OH H 1H-tetrazol-5-yl 196 C═CH₂ Cl Cl OH H N₃ 197 C═CH₂ Cl Cl OH HOCH₃ 198 C═CH₂ Cl Cl OH H CN 199 C═CH₂ Cl Cl OH H 1H-imidazol-1-yl 200C═CH₂ Cl Cl OH H 1H-imidazol-2-yl 201 C═CH₂ Cl Cl OH H 1H-imidazol-5-yl202 C═CH₂ Cl Cl OH H 1H-tetrazol-1-yl 203 C═CH₂ Cl Cl OH H2H-tetrazol-2-yl 204 C═CH₂ Cl Cl OH H 1H-tetrazol-5-yl 205 C═CH₂ Cl BrOH H H 206 C═CH₂ Cl Br OH H D 207 C═CH₂ Cl Br OH H F 208 C═CH₂ Cl Br OHH N₃ 209 C═CH₂ Cl Br OH H OCH₃ 210 C═CH₂ Cl Br OH H CN 211 C═CH₂ Cl BrOH H 1H-imidazol-1-yl 212 C═CH₂ Cl Br OH H 1H-imidazol-2-yl 213 C═CH₂ ClBr OH H 1H-imidazol-5-yl 214 C═CH₂ Cl Br OH H 1H-tetrazol-1-yl 215 C═CH₂Cl Br OH H 2H-tetrazol-2-yl 216 C═CH₂ Cl Br OH H 1H-tetrazol-5-yl 217C═CH₂ Br F OH H H 218 C═CH₂ Br F OH H D 219 C═CH₂ Br F OH H F 220 C═CH₂Br F OH H N₃ 221 C═CH₂ Br F OH H OCH₃ 222 C═CH₂ Br F OH H CN 223 C═CH₂Br F OH H 1H-imidazol-1-yl 224 C═CH₂ Br F OH H 1H-imidazol-2-yl 225C═CH₂ Br F OH H 1H-imidazol-5-yl 226 C═CH₂ Br F OH H 1H-tetrazol-1-yl227 C═CH₂ Br F OH H 2H-tetrazol-2-yl 228 C═CH₂ Br F OH H1H-tetrazol-5-yl 229 C═CH₂ Br Cl OH H H 230 C═CH₂ Br Cl OH H D 231 C═CH₂Br Cl OH H F 232 C═CH₂ Br Cl OH H N₃ 233 C═CH₂ Br Cl OH H OCH₃ 234 C═CH₂Br Cl OH H CN 235 C═CH₂ Br Cl OH H 1H-imidazol-1-yl 236 C═CH₂ Br Cl OH H1H-imidazol-2-yl 237 C═CH₂ Br Cl OH H 1H-imidazol-5-yl 238 C═CH₂ Br ClOH H 1H-tetrazol-1-yl 239 C═CH₂ Br Cl OH H 2H-tetrazol-2-yl 240 C═CH₂ BrCl OH H 1H-tetrazol-5-yl 241 C═CH₂ Br Br OH H H 242 C═CH₂ Br Br OH H D243 C═CH₂ Br Br OH H F 244 C═CH₂ Br Br OH H N₃ 245 C═CH₂ Br Br OH H OCH₃246 C═CH₂ Br Br OH H CN 247 C═CH₂ Br Br OH H 1H-imidazol-1-yl 248 C═CH₂Br Br OH H 1H-imidazol-2-yl 249 C═CH₂ Br Br OH H 1H-imidazol-5-yl 250C═CH₂ Br Br OH H 1H-tetrazol-1-yl 251 C═CH₂ Br Br OH H 2H-tetrazol-2-yl252 C═CH₂ Br Br OH H 1H-tetrazol-5-yl 253 C═CH₂ CH₃ CH₃ OH H H 254 C═CH₂CH₃ CH₃ OH H D 255 C═CH₂ CH₃ CH₃ OH H F 256 C═CH₂ CH₃ CH₃ OH H N₃ 257C═CH₂ CH₃ CH₃ OH H OCH₃ 258 C═CH₂ CH₃ CH₃ OH H CN 259 C═CH₂ CH₃ CH₃ OH H1H-imidazol-1-yl 260 C═CH₂ CH₃ CH₃ OH H 1H-imidazol-2-yl 261 C═CH₂ CH₃CH₃ OH H 1H-imidazol-5-yl 262 C═CH₂ CH₃ CH₃ OH H 1H-tetrazol-1-yl 263C═CH₂ CH₃ CH₃ OH H 2H-tetrazol-2-yl 264 C═CH₂ CH₃ CH₃ OH H1H-tetrazol-5-yl 265 C═CH₂ CH₃ CCH OH H N₃ 266 C═CH₂ CH₃ CCH OH H OCH₃267 C═CH₂ CH₃ CCH OH H CN 268 C═CH₂ CH₃ CCH OH H 1H-imidazol-1-yl 269C═CH₂ CH₃ CCH OH H 1H-imidazol-2-yl 270 C═CH₂ CH₃ CCH OH H1H-imidazol-5-yl 271 C═CH₂ CH₃ CCH OH H 1H-tetrazol-1-yl 272 C═CH₂ CH₃CCH OH H 2H-tetrazol-2-yl 273 C═CH₂ CH₃ CCH OH H 1H-tetrazol-5-yl 274C═CH₂ F CCH OH H N₃ 275 C═CH₂ F CCH OH H OCH₃ 276 C═CH₂ F CCH OH H CN277 C═CH₂ F CCH OH H 1H-imidazol-1-yl 278 C═CH₂ F CCH OH H1H-imidazol-2-yl 279 C═CH₂ F CCH OH H 1H-imidazol-5-yl 280 C═CH₂ F CCHOH H 1H-tetrazol-1-yl 281 C═CH₂ F CCH OH H 2H-tetrazol-2-yl 282 C═CH₂ FCCH OH H 1H-tetrazol-5-yl 283 C═CH₂ Cl CCH OH H H 284 C═CH₂ Cl CCH OH HD 285 C═CH₂ Cl CCH OH H F 286 C═CH₂ Cl CCH OH H N₃ 287 C═CH₂ Cl CCH OH HOCH₃ 288 C═CH₂ Cl CCH OH H CN 289 C═CH₂ Cl CCH OH H 1H-imidazol-1-yl 290C═CH₂ Cl CCH OH H 1H-imidazol-2-yl 291 C═CH₂ Cl CCH OH H1H-imidazol-5-yl 292 C═CH₂ Cl CCH OH H 1H-tetrazol-1-yl 293 C═CH₂ Cl CCHOH H 2H-tetrazol-2-yl 294 C═CH₂ Cl CCH OH H 1H-tetrazol-5-yl 295 C═CH₂Br CCH OH H H 296 C═CH₂ Br CCH OH H D 297 C═CH₂ Br CCH OH H F 298 C═CH₂Br CCH OH H N₃ 299 C═CH₂ Br CCH OH H OCH₃ 300 C═CH₂ Br CCH OH H CN 301C═CH₂ Br CCH OH H 1H-imidazol-1-yl 302 C═CH₂ Br CCH OH H1H-imidazol-2-yl 303 C═CH₂ Br CCH OH H 1H-imidazol-5-yl 304 C═CH₂ Br CCHOH H 1H-tetrazol-1-yl 305 C═CH₂ Br CCH OH H 2H-tetrazol-2-yl 306 C═CH₂Br CCH OH H 1H-tetrazol-5-yl 307 C═CH₂ CHF₂ CCH OH H H 308 C═CH₂ CHF₂CCH OH H D 309 C═CH₂ CHF₂ CCH OH H F 310 C═CH₂ CHF₂ CCH OH H N₃ 311C═CH₂ CHF₂ CCH OH H OCH₃ 312 C═CH₂ CHF₂ CCH OH H CN 313 C═CH₂ CHF₂ CCHOH H 1H-imidazol-1-yl 314 C═CH₂ CHF₂ CCH OH H 1H-imidazol-2-yl 315 C═CH₂CHF₂ CCH OH H 1H-imidazol-5-yl 316 C═CH₂ CHF₂ CCH OH H 1H-tetrazol-1-yl317 C═CH₂ CHF₂ CCH OH H 2H-tetrazol-2-yl 318 C═CH₂ CHF₂ CCH OH H1H-tetrazol-5-yl 319 C═CH₂ CH₂F CCH OH H H 320 C═CH₂ CH₂F CCH OH H D 321C═CH₂ CH₂F CCH OH H F 322 C═CH₂ CH₂F CCH OH H N₃ 323 C═CH₂ CH₂F CCH OH HOCH₃ 324 C═CH₂ CH₂F CCH OH H CN 325 C═CH₂ CH₂F CCH OH H 1H-imidazol-1-yl326 C═CH₂ CH₂F CCH OH H 1H-imidazol-2-yl 327 C═CH₂ CH₂F CCH OH H1H-imidazol-5-yl 328 C═CH₂ CH₂F CCH OH H 1H-tetrazol-1-yl 329 C═CH₂ CH₂FCCH OH H 2H-tetrazol-2-yl 330 C═CH₂ CH₂F CCH OH H 1H-tetrazol-5-yl

As shown below, each compound number in Table 1 can represent compoundsof different formulas but with the same X, R₁, R₂, R₃, R₄ and R₅moieties.

In another aspect, the present invention features compounds havingFormula II, and pharmaceutically acceptable salts thereof, as well asprodrugs thereof,

wherein for each compound of Formula II, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1.

In still another aspect, the present invention features compounds havingFormula III, and pharmaceutically acceptable salts thereof, as well asprodrugs thereof,

wherein for each compound of Formula III, X, R₁, R₂, R₃, R₄ and R₅ areas defined in Table 1.

In still another aspect, the present invention features phosphoramidateprodrugs of compounds having Formula III′,

wherein for each compound of Formula III′, X, R₁, R₂, R₃, R₄ and R₅ areas defined in Table 1.

In yet another aspect, the present invention features compounds havingFormula IV,

wherein for each compound of Formula IV, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1.

In yet another aspect, the present invention features compounds havingFormula V,

wherein for each compound of Formula V, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1.

In yet another aspect, the present invention features compounds havingFormula VI, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula VI, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1, and wherein P₁ is (HO)₂P(O)—O—P(O)(OH)—.

In yet another aspect, the present invention features compounds havingFormula VI′, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula VI′, X, R₁, R₂, R₃, R₄ and R₅ areas defined in Table 1, and wherein P₁ is (O⁻)₂P(O)—O—P(O)(O⁻)—.

In yet another aspect, the present invention features compounds havingFormula VI″, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula VI″, X, R₁, R₂, R₃, R₄ and R₅ areas defined in Table 1, and wherein P₁ is a protected monophosphateprodrug substitution. Non-limiting examples of suitable P₁ for FormulaVI″ can be selected from Table 2:

TABLE 2 Suitable P₁ for Formula VI″

As used herein, when a moiety is selected from a list or a table, thatmoiety can be any one of the moieties in the list or table. Forinstance, if a moiety in a formula is selected from A, B or C, then themoiety in the formula can be A. For another instance, if a moiety in aformula is selected from A, B or C, then the moiety in the formula canbe B. For yet another instance, if a moiety in a formula is selectedfrom A, B or C, then the moiety in the formula can be C.

In a further aspect, the present invention features compounds havingFormula VII, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula VII, X, R₁, R₂, R₃, R₄ and R₅ areas defined in Table 1.

In a further aspect, the present invention features compounds havingFormula VIII, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula VIII, X, R₁, R₂, R₃, R₄ and R₅ areas defined in Table 1.

In a further aspect, the present invention features compounds havingFormula IX, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula IX, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1.

In a further aspect, the present invention features compounds havingFormula A, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula A, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1. As compared to many other prodrug moieties, theprodrug moiety in Formula A can provide unexpectedly high triphosphateactive levels in both human hepatocytes and dog liver.

In a further aspect, the present invention features compounds havingFormula A′, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula A′, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1. As compared to many other prodrug moieties, theprodrug moiety in Formula A can provide unexpectedly high triphosphateactive levels in both human hepatocytes and dog liver.

In a further aspect, the present invention features compounds havingFormula A″, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula A″, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1. As compared to many other prodrug moieties, theprodrug moiety in Formula A can provide unexpectedly high triphosphateactive levels in both human hepatocytes and dog liver.

In a further aspect, the present invention features compounds havingFormula B, and pharmaceutically acceptable salts thereof,

wherein for each compound of Formula A, X, R₁, R₂, R₃, R₄ and R₅ are asdefined in Table 1.

The present invention also features compounds with any formula describedherein, wherein X, R₁, R₂, R₃, R₄ and R₅ moieties are as defined inTable 1, except that one Cl at R₁, R₂, R₃, R₄ or R₅ is replaced with Br,or preferably one Cl at R₁ or R₂ is replaced with Br.

The present invention also features compounds with any formula describedherein, wherein X, R₁, R₂, R₃, R₄ and R₅ moieties are as defined inTable 1, except that two Cl at R₁, R₂, R₃, R₄ or R₅ are replaced withBr, or preferably two Cl at R₁ or R₂ are replaced with Br.

The present invention also features compounds with any formula describedherein, wherein X, R₁, R₂, R₃, R₄ and R₅ moieties are as defined inTable 1, except that one F at R₁, R₂, R₃, R₄ or R₅ is replaced with Br,or preferably one F at R₁ or R₂ is replaced with Br.

The present invention also features compounds with any formula describedherein, wherein X, R₁, R₂, R₃, R₄ and R₅ moieties are as defined inTable 1, except that two F at R₁, R₂, R₃, R₄ or R₅ are replaced with Br,or preferably two F at R₁ or R₂ are replaced with Br.

The present invention also features compounds with any formula describedherein, wherein X, R₁, R₂, R₃, R₄ and R₅ moieties are as defined inTable 1, except that R₃ is

The present invention also features compounds with any formula describedherein, wherein X, R₁, R₂, R₃, R₄ and R₅ moieties are as defined inTable 1, except that R₃ is

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula I. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula II. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula III. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula III′. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula IV. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula V. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula VI. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula VI′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula VI″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula VII. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula VIII. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula IX. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula A. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula A′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula A″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 52according to Table 1, wherein the compound has Formula B. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula I. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula II. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula III. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula III′. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula IV. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula V. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula VI. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula VI′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula VI″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula VII. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula VIII. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula IX. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula A. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula A′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula A″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 64according to Table 1, wherein the compound has Formula B. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula I. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula II. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula III. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula III′. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula IV. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula V. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula VI. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula VI′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula VI″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula VII. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula VIII. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula IX. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula A. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula A′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula A″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 40according to Table 1, wherein the compound has Formula B. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula I.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula II.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula III.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula III′.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula IV.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula V.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula VI.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula VI′.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula VI″.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula VII.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula VIII.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula IX.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula A.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula A′.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula A″.

In another aspect, the present invention features Compound No. 35according to Table 1, wherein the compound has Formula B.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula I.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula II.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula III.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula III′.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula IV.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula V.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula VI.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula VI′.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula VI″.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula VII.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula VIII.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula IX.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula A.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula A′.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula A″.

In another aspect, the present invention features Compound No. 43according to Table 1, wherein the compound has Formula B.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula I.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula II.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula III.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula III′.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula IV.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula V.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula VI.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula VI′.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula VI″.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula VII.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula VIII.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula IX.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula A.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula A′.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula A″.

In another aspect, the present invention features Compound No. 47according to Table 1, wherein the compound has Formula B.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula I.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula II.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula III.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula III′.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula IV.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula V.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula VI.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula VI′.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula VI″.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula VII.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula VIII.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula IX.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula A.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula A′.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula A″.

In another aspect, the present invention features Compound No. 59according to Table 1, wherein the compound has Formula B.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula I. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula II. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula III. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula III′. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula IV. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula V. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula VI. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula VI′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula VI″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula VII. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula VIII. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula IX. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula A. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula A′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula A″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 215according to Table 1, wherein the compound has Formula B. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula I. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula II. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula III. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula III′. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula IV. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula V. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula VI. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula VI′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula VI″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula VII. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula VIII. Thecompound according to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula IX. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula A. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula A′. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula A″. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

In another aspect, the present invention features Compound No. 216according to Table 1, wherein the compound has Formula B. The compoundaccording to this aspect of the invention is expected to havesignificantly improved permeability as compared to compounds in which Bris replaced with Cl.

Likewise, in another aspect, the present invention features Compound No.1 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.2 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.9 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.10 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.127 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.128 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.129 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.130 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.11 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.12 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.13 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.14 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.131 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.132 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.133 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

Likewise, in another aspect, the present invention features Compound No.134 according to Table 1, wherein the compound has Formula I, II, III,III′, IV, V, VI, VI′, VI″, VII, VIII, IX, A, A′, A″ or B.

In yet another embodiment, the present invention features a compoundselected from Table 3. Some of the compounds in Table 3 showedsignificantly improved intracellular triphosphate drug concentrations inreplicon wash-out experiments, as compared to the compound of Example 1.For the replicon wash-out experiments, cells were incubated for 4 hourswith the prodrug, and the concentration of the triphosphate drug in thecells was measured at 24-hour.

TABLE 3 Exemplary Compounds

In yet another embodiment, the present invention features a compound thecompound selected from Table 4. Table 4 has the same compound list asTable 3, except that for each compound in Table 3, Cl and Br arereplaced with Br and F, respectively, in Table 4.

Any compound according to any of the above-described aspects can beprepared and used in prodrug forms. A suitable prodrug has chemically ormetabolically cleavable group(s) and becomes, by solvolysis or underphysiological conditions, a compound that is pharmaceutically active invivo. A prodrug can be formed in a conventional manner by reaction of afunctional group of the compound (such as an amino, hydroxy or carboxygroup). Prodrugs often offer advantages of better metabolism, potency,solubility, tissue compatibility, or delayed release in mammals.Prodrugs include acid derivatives well known to practitioners of theart, such as, for example, esters prepared by reaction of the parentacidic compound with a suitable alcohol, or amides prepared by reactionof the parent acid compound with a suitable amine. Examples of prodrugsinclude, but are not limited to, acetate, formate, benzoate or otheracylated derivatives of alcohol or amine functional groups within thecompounds of the invention. For example, prodrugs can be aliphatic oraromatic esters derived from acidic groups on a compound of theinvention. For another example, prodrugs can be aliphatic or aromaticesters of hydroxyl or amino groups on a compound of the invention.Phosphate prodrugs of hydroxyl groups are preferred prodrugs.Preferably, prodrugs used herein are phosphoramidate prodrugs.Non-limiting examples of suitable prodrug moieties are provided in Table2, as described hereinabove.

In yet another aspect, any compound, salt or prodrug according to anyaspect, embodiment, example and preference described herein can beisotopically substituted. Preferred isotopic substitutions includesubstitutions with stable or nonradioactive isotopes such as deuterium,¹³C, ¹⁵N or ¹⁸O. Incorporation of a heavy atom, such as substitution ofdeuterium for hydrogen, can give rise to an isotope effect that couldalter the pharmacokinetics of the drug. In one example, at least 5 mol %(e.g., at least 10 mol %) of hydrogen in a compound of the presentinvention is substituted with deuterium. In another example, at least 25mole % of hydrogen in a compound of the present invention is substitutedwith deuterium. In a further example, at least 50, 60, 70, 80 or 90 mole% of hydrogen in a compound of the present invention is substituted withdeuterium. The natural abundance of deuterium is about 0.015%. Deuteriumsubstitution or enrichment can be achieved, without limitation, byeither exchanging protons with deuterium or by synthesizing the moleculewith enriched or substituted starting materials. Other methods known inthe art can also be used for isotopic substitutions.

In another aspect, the present invention features methods of using anycompound/salt/prodrug according to any aspect, embodiment, example andpreference described herein (e.g., the compound of Example 1, Example 3,Example 5, Example 6, Example 7 or Example 41, or a pharmaceuticallyacceptable salt thereof) to treat HCV infection. Such a compound, saltor prodrug has inhibitory activity against HCV polymerase. The methodcomprises administering an effective amount of such a compound, salt orprodrug to an HCV patient in need thereof. In one embodiment, thepatient is infected with HCV genotype 1. In another embodiment, thepatient is infected with HCV genotype 2. In yet another embodiment, thepatient is infected with HCV genotype 3. In yet another embodiment, thepatient is infected with HCV genotype 4. In yet another embodiment, thepatient is infected with HCV genotype 5. In yet another embodiment, thepatient is infected with HCV genotype 6.

It is contemplated that different compounds of the invention may havedifferent anti-viral activities and/or toxicity/safety profiles.Compounds with less antiviral activities can be dosed more frequentlyand/or with greater amounts. Compounds with higher antiviral activitiescan be dosed less frequently and/or with lesser amounts. Moreover, acompound that does not have a commercially desired toxicity/safetyprofile does not prevent its utility under patent law as an anti-viralagent, despite the fact that the US FDA might not approve it for humantreatment due to the agency's benefit-cost analyses and/or othernon-patent related concerns.

In yet another aspect, the present invention features methods fortreating HCV infection in a subject in need of such treatment. Themethods comprise administering at least two direct acting antiviralagents (DAAs) to the subject for a duration of no more than 12 weeks, orfor another duration as set forth herein. Said at least two DAAscomprise (1) a compound/salt/prodrug according to any aspect,embodiment, example and preference described herein (e.g., the compoundof Example 1, 3, 6 or 7, or a pharmaceutically acceptable salt thereof),and (2) another DAA. The other DAA can be, for example, selected from anHCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5Ainhibitor, or a cyclophilin inhibitor. Preferably, the other DAA is anHCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5Ainhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, suchas those described in US Patent Application Publication Nos.2010/0317568 and 2012/0004196, both of which are incorporated herein byreference in their entireties. Highly preferably, the other DAA is thecompound of Example 35 of US Patent Application Publication No.2010/0317568. Also, highly preferably, the other DAA is the compound ofExample 3.52 of US Patent Application Publication No. 2012/0004196. Inone example, the duration of the treatment is 12 weeks. The duration ofthe treatment can also be, for example, no more than 8 weeks.Preferably, the two or more DAAs are administered in amounts effectiveto provide a sustained virological response (SVR) or achieve anotherdesired measure of effectiveness in the subject. The subject is notadministered ribavirin during the treatment regimen. The subject is alsonot administered interferon during the treatment regimen. Put anotherway, the methods exclude the administration of interferon or ribavirinto the subject, thereby avoiding the side effects associated withinterferon and ribavirin.

In another aspect, the present invention features methods for treating apopulation of subjects having HCV infection. The methods compriseadministering at least two DAAs to the subjects for a duration of nomore than 12 weeks. Said at least two DAAs comprise (1) acompound/salt/prodrug according to any aspect, embodiment, example andpreference described herein (e.g., the compound of Example 1, 3, 6 or 7,or a pharmaceutically acceptable salt thereof), and (2) another DAA. Theother DAA can be, for example, selected from an HCV protease inhibitor,an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilininhibitor. Preferably, the other DAA is an HCV protease inhibitor, anHCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, theother DAA is an HCV NS5A inhibitor, such as those described in US PatentApplication Publication Nos. 2010/0317568 and 2012/0004196, both ofwhich are incorporated herein by reference in their entireties. Highlypreferably, the other DAA is the compound of Example 35 of US PatentApplication Publication No. 2010/0317568. Also, highly preferably, theother DAA is the compound of Example 3.52 of US Patent ApplicationPublication No. 2012/0004196. Preferably, said at least two DAAs areadministered to the subjects in amounts effective to result in SVR oranother measure of effectiveness in at least about 70% of thepopulation, preferably at least about 80% of the population, or morepreferably at least about 90% of the population. The subjects are notadministered ribavirin during the treatment regimen. The subjects arealso not administered interferon during the treatment regimen. Putanother way, the methods exclude the administration of interferon orribavirin to the subject, thereby avoiding the side effects associatedwith interferon and ribavirin.

Non-limiting examples of the other DAAs include PSI-7977 (sofosbuvir),PSI-938, BMS-790052 (daclatasvir), BMS-650032 (asunaprevir), BMS-791325,GS-5885 (ledipasvir), GS-9451 (tegobuvir), GS-9190, GS-9256, BI-201335,BI-27127, telaprevir, VX-222, TMC-435 (simepravir), MK-5172, MK-7009(vaniprevir), danoprevir, paritaprevir, ombitasvir, ABT-493, and R7128(mericitabine).

In any method described herein, the DAAs can be administered in anyeffective dosing schemes and/or frequencies; for example, they can eachbe administered daily. Each DAA can be administered either separately orin combination, and each DAA can be administered once a day, twice aday, or three times a day. Preferably, the DAAs employed herein areadministered once daily.

In yet another aspect, the present invention features a combination of acompound/salt/prodrug according to any aspect, embodiment, example andpreference described herein (e.g., the compound of Example 1, 3, 6 or 7,or a pharmaceutically acceptable salt thereof), and another DAA, for useto treat HCV infection. The other DAA can be, for example, selected froman HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5Ainhibitor, or a cyclophilin inhibitor. Preferably, the other DAA is anHCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5Ainhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, suchas those described in US Patent Application Publication Nos.2010/0317568 and 2012/0004196, both of which are incorporated herein byreference in their entireties. Highly preferably, the other DAA is thecompound of Example 35 of US Patent Application Publication No.2010/0317568. Also, highly preferably, the other DAA is the compound ofExample 3.52 of US Patent Application Publication No. 2012/0004196. Thetreatment comprises administering the DAAs to a subject infected withHCV. The duration of the treatment regimen is no more than twelve weeks(e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8,7, 6, 5, 4, or 3 weeks). Preferably, the duration of the treatmentregimen is twelve weeks. The duration of the treatment can also last,for example, no more than eight weeks (e.g., the duration being 8 weeks;or the duration being 7, 6, 5, 4, or 3 weeks). The treatment does notinclude administering interferon or ribavirin. The DAAs can beadministered concurrently or sequentially. Preferably, the DAAs areadministered once daily. As a non-limiting example, the patient beingtreated is infected with HCV genotype 1, such as genotype 1a or 1b. Asanother non-limiting example, the patient is infected with HCV genotype2. As another non-limiting example, the patient is infected with HCVgenotype 3. As another non-limiting example, the patient is infectedwith HCV genotype 4. As another non-limiting example, the patient isinfected with HCV genotype 5. As another non-limiting example, thepatient is infected with HCV genotype 6. As yet another non-limitingexample, the patient is a HCV-treatment naïve patient, a HCV-treatmentexperienced patient, an interferon non-responder (e.g., a nullresponder), or not a candidate for interferon treatment. As used in thisapplication, the interferon non-responder patients include partialinterferon responders and interferon rebound patients. See GUIDANCE FORINDUSTRY—CHRONIC HEPATITIS C VIRUS INFECTION: DEVELOPING DIRECT-ACTINGANTIVIRAL AGENTS FOR TREATMENT (FDA, September 2010, draft guidance) forthe definitions of naïve, partial responder, responder relapser (i.e.,rebound), and null responder patients. The interferon non-responderpatients also include null responder patients. In one example of thisaspect of the invention, the treatment lasts for 12 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 1.In another example, the treatment lasts for 11 weeks, and the subjectbeing treated is a naïve patient infected with HCV genotype 1. In stillanother example, the treatment lasts for 10 weeks, and the subject beingtreated is a naïve patient infected with HCV genotype 1. In yet anotherexample, the treatment lasts for 9 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 1. In yet another example,the treatment lasts for 8 weeks, and the subject being treated is anaïve patient infected with HCV genotype 1. In yet another example, thetreatment lasts for 7 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 6 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 5 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 4 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 3 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is a naïvepatient infected with HCV genotype. In another example, the treatmentlasts for 11 weeks, and the subject being treated is a naïve patientinfected with HCV selected from genotypes 2, 3, 4, 5 or 6. In stillanother example, the treatment lasts for 10 weeks, and the subject beingtreated is a naïve patient infected with HCV selected from genotypes 2,3, 4, 5 or 6. In yet another example, the treatment lasts for 9 weeks,and the subject being treated is a naïve patient infected with HCVselected from genotypes 2, 3, 4, 5 or 6. In yet another example, thetreatment lasts for 8 weeks, and the subject being treated is a naïvepatient infected with selected from genotypes 2, 3, 4, 5 or 6. In yetanother example, the treatment lasts for 7 weeks, and the subject beingtreated is a naïve patient infected with selected from genotypes 2, 3,4, 5 or 6. In yet another example, the treatment lasts for 6 weeks, andthe subject being treated is a naïve patient infected with selected fromgenotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lastsfor 5 weeks, and the subject being treated is a naïve patient infectedwith selected from genotypes 2, 3, 4, 5 or 6. In yet another example,the treatment lasts for 4 weeks, and the subject being treated is anaïve patient infected with selected from genotypes 2, 3, 4, 5 or 6. Inyet another example, the treatment lasts for 3 weeks, and the subjectbeing treated is a naïve patient infected with selected from genotypes2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 12weeks, and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In another example, thetreatment lasts for 11 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Instill another example, the treatment lasts for 10 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1. In yet another example, the treatment lasts for 9 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 8 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 7 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1. In yet another example, the treatment lasts for 6 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 5 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 4 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1. In yet another example, the treatment lasts for 3 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV selected fromgenotype 2, 3, 4, 5 or 6. In another example, the treatment lasts for 11weeks, and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. Instill another example, the treatment lasts for 10 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV selected from genotype 2, 3, 4, 5 or 6. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV selected fromgenotype 2, 3, 4, 5 or 6. In yet another example, the treatment lastsfor 8 weeks, and the subject being treated is a non-responder (e.g., anull responder) infected with HCV selected from genotype 2, 3, 4, 5 or6. In yet another example, the treatment lasts for 7 weeks, and thesubject being treated is a non-responder (e.g., a null responder)infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet anotherexample, the treatment lasts for 6 weeks, and the subject being treatedis a non-responder (e.g., a null responder) infected with HCV selectedfrom genotype 2, 3, 4, 5 or 6. In yet another example, the treatmentlasts for 5 weeks, and the subject being treated is a non-responder(e.g., a null responder) infected with HCV selected from genotype 2, 3,4, 5 or 6. In yet another example, the treatment lasts for 4 weeks, andthe subject being treated is a non-responder (e.g., a null responder)infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet anotherexample, the treatment lasts for 3 weeks, and the subject being treatedis a non-responder (e.g., a null responder) infected with HCV selectedfrom genotype 2, 3, 4, 5 or 6.

A treatment regimen of the present invention generally constitutes acomplete treatment regimen, i.e., no subsequent interferon-containingregimen is intended. Thus, a treatment or use described herein generallydoes not include any subsequent interferon-containing treatment.Preferably, a treatment or use described herein does not include anysubsequent ribavirin-containing treatment.

The methods of the present invention can provide effective treatment ofHCV infection without the use of interferon or ribavirin and for ashorter period of time, for example and without limitation, a treatmentduration of no more than twelve weeks, alternatively no more than elevenweeks, alternatively no more than ten weeks, alternatively no more thannine weeks, alternatively no more than eight weeks, alternatively nomore than seven weeks, alternatively no more than six weeks,alternatively no more than five weeks, alternatively no more than fourweeks, or alternatively, no more than three weeks.

In one aspect, the present invention features methods for treating HCVinfection in a subject comprising administering at least two DAAs, inthe absence of interferon and ribavirin, to the subject for a durationof no more than twelve weeks, alternatively no more than eight weeks.Put another way, the methods exclude interferon and ribavirin. Said atleast two DAAs comprise a compound/salt/prodrug according to any aspect,embodiment, example and preference described herein (e.g., the compoundof Example 1, 3, 6 or 7, or a pharmaceutically acceptable salt thereof),and another DAA, which can be co-administered, or administeredseparately or independently, with the same or different dosingfrequencies. Preferably, said at least two DAAs are administered once aday. They can also be administered, for example, twice a day or threetimes a day. The other DAA can be, for example, selected from an HCVprotease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor,or a cyclophilin inhibitor. Preferably, the other DAA is an HCV proteaseinhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. Morepreferably, the other DAA is an HCV NS5A inhibitor, such as thosedescribed in US Patent Application Publication Nos. 2010/0317568 and2012/0004196. Highly preferably, the other DAA is the compound ofExample 35 of US Patent Application Publication No. 2010/0317568. Also,highly preferably, the other DAA is the compound of Example 3.52 of USPatent Application Publication No. 2012/0004196.

Various measures may be used to express the effectiveness of a method ofthe present invention. One such measure is SVR, which, as used herein,means that the virus is undetectable at the end of therapy and for atleast 8 weeks after the end of therapy (SVR8); preferably, the virus isundetectable at the end of therapy and for at least 12 weeks after theend of therapy (SVR12); more preferably, the virus is undetectable atthe end of therapy and for at least 16 weeks after the end of therapy(SVR16); and highly preferably, the virus is undetectable at the end oftherapy and for at least 24 weeks after the end of therapy (SVR24).SVR24 is often considered as a functional definition of cure; and a highrate of SVR at less than 24 week post-treatment (e.g., SVR8 or SVR12)can be predictive of a high rate of SVR24.

In some embodiments, a treatment regimen of the invention comprisestreating a population of subjects having HCV infection (e.g. treatmentnaïve subjects), and the regimen comprises administering at least twoDAAs to the subjects for a duration of no more than 12 weeks, or foranother duration disclosed herein, wherein said at least two DAAscomprise a compound/salt/prodrug according to any aspect, embodiment,example and preference described herein (e.g., the compound of Example1, 3, 6 or 7, or a pharmaceutically acceptable salt thereof), andanother DAA, and are administered to the subjects in amounts effectiveto provide an SVR (e.g., SVR12 or SVR24) in at least about 70% of thepopulation, alternatively at least about 75% of the population,alternatively at least about 80% of the population, alternatively atleast about 85% of the population, alternatively at least about 90% ofthe population, alternatively at least about 95% of the population,alternatively about 100% of the population. The other DAA can be, forexample, selected from an HCV protease inhibitor, an HCV polymeraseinhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor.Preferably, the other DAA is an HCV protease inhibitor, an HCVpolymerase inhibitor, or an HCV NS5A inhibitor. More preferably, theother DAA is an HCV NS5A inhibitor, such as those described in US PatentApplication Publication Nos. 2010/0317568 and 2012/0004196. Highlypreferably, the other DAA is the compound of Example 35 of US PatentApplication Publication No. 2010/0317568. Also, highly preferably, theother DAA is the compound of Example 3.52 of US Patent ApplicationPublication No. 2012/0004196.

In some embodiments, a treatment regimen of the invention comprisestreating a population of IFN experienced subjects (e.g., interferonnon-responders) having HCV infection, and the method comprisesadministering at least two DAAs to the subjects for a duration of nomore than 12 weeks, or for another duration disclosed herein, whereinsaid at least two DAAs comprise (1) a compound/salt/prodrug according toany aspect, embodiment, example and preference described herein(hereinafter “Compound 1”, which preferably is the compound of Example 1or Example 3 or Example 6 or Example 41 or a pharmaceutically acceptablesalt thereof), and another DAA (hereinafter “Compound 2”), and areadministered to the subjects in amounts effective to provide an SVR(e.g., SVR12 or SVR24) in at least about 50% of the population,alternatively at least about 55% of the population, alternatively atleast about 60% of the population, alternatively at least about 65% ofthe population, alternatively at least about 70% of the population,alternatively at least about 75% of the population, alternatively atleast about 80% of the population, alternatively at least about 85% ofthe population, alternatively at least about 90% of the population,alternatively at least about 95% of the population, or alternativelyabout 100% of the population.

In any aspect, embodiment, example and preference described herein,Compound 2 can be, for example, selected from an HCV protease inhibitor,an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilininhibitor. Preferably, Compound 2 is an HCV protease inhibitor, an HCVpolymerase inhibitor, or an HCV NS5A inhibitor. More preferably,Compound 2 is an HCV NS5A inhibitor, such as those described in USPatent Application Publication Nos. 2010/0317568 and 2012/0004196.Highly preferably, Compound 2 is the compound of Example 35 of US PatentApplication Publication No. 2010/0317568. Also, highly preferably,Compound 2 is the compound of Example 3.52 of US Patent ApplicationPublication No. 2012/0004196.

In one aspect, the present invention features a method of treating HCVinfection, comprising administering to a patient in need thereof aneffective amount of a combination of at least two DAAs, wherein said atleast two DAAs comprise Compound 1 and Compound 2. The treatment lasts 8weeks and does not include administration of any interferon orribavirin. The DAAs can be administered at the same or different dosingfrequencies. The patient being treated can be a treatment naïve patient;a treatment experienced patient, including, but not limited to, arelapser, an interferon partial responder, an interferon non-responder,or a null responder; or a patient unable to take interferon. The patientmay be infected with, for example and without limitation, HCV genotype1, such as HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 or 3;or HCV genotype 4, 5 or 6. The treatment according to this aspect of thetechnology may also be effective against other HCV genotypes. The DAAscan be administered around the same time or at different times. Inaddition to Compound 1 and Compound 2, said at least two DAAs can alsoinclude one or more additional DAAs selected from, for example, HCVprotease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.Non-limiting examples of such additional DAAs include PSI-7977, PSI-938,TMC-435, BMS-790052, BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335,BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.

In another aspect, the present invention features a method of treatingHCV infection, comprising administering to a patient in need thereof aneffective amount of a combination of at least two DAAs, wherein said atleast two DAAs comprise Compound 1 and Compound 2. The treatment lasts 7weeks and does not include administration of any interferon orribavirin. The DAAs can be administered at the same or different dosingfrequencies. The patient being treated can be a treatment naïve patient;a treatment experienced patient, including, but not limited to, arelapser, an interferon partial responder, an interferon non-responder,or a null responder; or a patient unable to take interferon. The patientmay be infected with, for example and without limitation, HCV genotype1, such as HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 or 3;or HCV genotype 4, 5 or 6. The treatment according to this aspect of thetechnology may also be effective against other HCV genotypes. The DAAscan be administered around the same time or at different times. Inaddition to Compound 1 and Compound 2, said at least two DAAs can alsoinclude one or more additional DAAs selected from, for example, HCVprotease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.Non-limiting examples of such additional DAAs include PSI-7977, PSI-938,TMC-435, BMS-790052, BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335,BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 6 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 5 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 4 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 3 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 24 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 13 to 23 weeks (e.g., the duration of the treatment isselected from 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 weeks) anddoes not include administration of any interferon or ribavirin. The DAAscan be administered at the same or different dosing frequencies. Thepatient being treated can be a treatment naïve patient; a treatmentexperienced patient, including, but not limited to, a relapser, aninterferon partial responder, an interferon non-responder, or a nullresponder; or a patient unable to take interferon. The patient may beinfected with, for example and without limitation, HCV genotype 1, suchas HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 or 3; or HCVgenotype 4, 5 or 6. The treatment according to this aspect of thetechnology may also be effective against other HCV genotypes. The DAAscan be administered around the same time or at different times. Inaddition to Compound 1 and Compound 2, said at least two DAAs can alsoinclude one or more additional DAAs selected from, for example, HCVprotease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.Non-limiting examples of such additional DAAs include PSI-7977, PSI-938,TMC-435, BMS-790052, BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335,BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 12 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir. As used in this application, a HCVpolymerase inhibitor can be a nucleoside polymerase inhibitor, anucleotide polymerase inhibitor, a non-nucleoside polymerase inhibitor,or a non-nucleotide polymerase inhibitor.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 11 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 10 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir.

In yet another aspect, the present invention features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of at least two DAAs,wherein said at least two DAAs comprise Compound 1 and Compound 2. Thetreatment lasts 9 weeks and does not include administration of anyinterferon or ribavirin. The DAAs can be administered at the same ordifferent dosing frequencies. The patient being treated can be atreatment naïve patient; a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder, or a null responder; or a patient unable totake interferon. The patient may be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. Thetreatment according to this aspect of the technology may also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times. In addition to Compound 1and Compound 2, said at least two DAAs can also include one or moreadditional DAAs selected from, for example, HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples ofsuch additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052,BMS-650032, GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, telaprevir,VX-222, mericitabine, and danoprevir.

A method of the present invention can be used to treat a naïve patientor a treatment experienced patient. Treatment experienced patientsinclude interferon non-responders (e.g., null responders), partialresponders, and relapsers. A method of the present invention can also beused to treat patients who are not candidates for interferon treatment.Patients who are not candidates for interferon treatment include, butare not limited to, one or more of the following groups: patientsintolerant to interferon, patients who refuse to take interferontreatment, patients with medical conditions which preclude them fromtaking interferon, and patients who have an increased risk of sideeffects or infection by taking interferon.

In any method described herein, one or more additional DAAs can beoptionally used in the treatment regimen in addition to Compound 1 andCompound 2. These additional DAAs can be HCV protease inhibitors, HCVnucleoside or nucleotide polymerase inhibitors, HCV non-nucleosidepolymerase inhibitors, HCV NS3B inhibitors, HCV NS4A inhibitors, HCVNS5A inhibitors, HCV NS5B inhibitors, HCV entry inhibitors, cyclophilininhibitors, or combinations thereof.

Preferred HCV protease inhibitors for this purpose include, but are notlimited to, telaprevir (Vertex), boceprevir (Merck), BI-201335(Boehringer Ingelheim), GS-9451 (Gilead), and BMS-650032 (BMS). Othersuitable protease inhibitors include, but are not limited to, ACH-1095(Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL-181(Avila), AVL-192 (Avila), BMS-650032 (BMS), danoprevir (RG7227/ITMN-191,Roche), GS-9132 (Gilead), GS-9256 (Gilead), IDX-136 (Idenix), IDX-316(Idenix), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir(Schering-Plough Corp), PHX-1766 (Phenomix), TMC-435 (Tibotec),vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-500 (Vertex), VX-813(Vertex), VX-985 (Vertex), or a combination thereof.

Preferred non-nucleoside HCV polymerase inhibitors for use in thepresent invention include, but are not limited to, GS-9190 (Gilead),BI-207127 (Boehringer Ingelheim), and VX-222 (VCH-222) (Vertex &ViraChem). Preferred nucleotide HCV polymerase inhibitors include, butare not limited to, PSI-7977 (Gilead), and PSI-938 (Gilead). Othersuitable and non-limiting examples of suitable HCV polymerase inhibitorsinclude ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941(Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo),GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck),tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916(ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX-102 (Idenix), IDX-184(Idenix), INX-189 (Inhibitex), MK-0608 (Merck), RG7128 (Roche), TMC64912(Medivir), GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst), ALS-2200(Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or acombination thereof. A polymerase inhibitor may be a nucleoside ornucleotide polymerase inhibitor, such as GS-6620 (Gilead), IDX-102(Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck),PSI-7977 (Gilead), PSI-938 (Gilead), RG7128 (Roche), TMC64912 (Medivir),ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), ora combination therefore. A polymerase inhibitor may also be anon-nucleoside polymerase inhibitor, such as PF-00868554 (Pfizer),ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941(Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo),GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck),tegobuvir (Gilead), TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem),VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759(Vertex), or a combination thereof.

Preferred NS5A inhibitors include, but are not limited to, BMS-790052(BMS) and GS-5885 (Gilead). Non-limiting examples of suitable NS5Ainhibitors include GSK62336805 (GlaxoSmithKline), ACH-2928 (Achillion),AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BMS-790052 (BMS),BMS-824393 (BMS), GS-5885 (Gilead), PPI-1301 (Presidio), PPI-461(Presidio) A-831 (Arrow Therapeutics), A-689 (Arrow Therapeutics) or acombination thereof.

Non-limiting examples of suitable cyclophilin inhibitors includealisporovir (Novartis & Debiopharm), NM-811 (Novartis), SCY-635(Scynexis), or a combination thereof.

Non-limiting examples of suitable HCV entry inhibitors include ITX-4520(iTherx), ITX-5061 (iTherx), or a combination thereof.

Specific examples of other DAA agents that are suitable for inclusion ina method of the present invention include, but are not limited to,AP-H005, A-831 (Arrow Therapeutics) (NS5A inhibitor), A-689 (ArrowTherapeutics) (NS5A inhibitor), INX08189 (Inhibitex) (polymeraseinhibitor), ITMN-191 (Intermune/Roche) (NS3/4A Protease inhibitor),VBY-376 (Protease Inhibitor) (Virobay), ACH-1625 (Achillion, Proteaseinhibitor), IDX136 (Idenix, Protease Inhibitor), IDX316 (Idenix,Protease inhibitor), VX-813 (Vertex), SCH 900518 (Schering-Plough),TMC-435 (Tibotec), ITMN-191 (Intermune, Roche), MK-7009 (Merck), IDX-PI(Novartis), R7128 (Roche), PF-868554 (Pfizer) (non-nucleoside polymeraseinhibitor), PF-4878691 (Pfizer), IDX-184 (Idenix), IDX-375 (Idenix, NS5Bpolymerase inhibitor), PPI-461 (Presidio), BILB-1941 (BoehringerIngelheim), GS-9190 (Gilead), BMS-790052 (BMS), CTS-1027 (Conatus),GS-9620 (Gilead), PF-4878691 (Pfizer), RO5303253 (Roche), ALS-2200(Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), GSK62336805(GlaxoSmithKline), or any combinations thereof.

In some embodiments, the present invention features methods for treatingpatients infected with HCV genotype 1, such as 1a or 1b. The methodscomprise administering to such a patient a combination of at least 2DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), suchas no more than 8 weeks (e.g., the duration being 8 weeks), wherein thetreatment does not include administration of either interferon orribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2.Compound 1 and Compound 2 can be administered in therapeuticallyeffective amounts to provide a SVR (for example, SVR12 or SVR24) afterthe completion of the treatment. The patients may be treatment naïvepatients or treatment experienced patients. The treatment duration canbe no more than 12 weeks, including but not limited to, no more than 11weeks, no more than 10 weeks, no more than 9 weeks, but preferably nomore than 8 weeks, no more than 7 weeks, no more than 6 weeks, no morethan 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., theduration being 12 weeks, or the duration being 8 weeks.

In some embodiments, the present invention features methods for treatingpatients with HCV genotype 2 or 3 infection. The methods compriseadministering to such a patient a combination of at least 2 DAAs for nomore than 12 weeks (e.g., the duration being 12 weeks), such as no morethan 8 weeks (e.g., the duration being 8 weeks), wherein the treatmentdoes not include administration of either interferon or ribavirin, andsaid at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 andCompound 2 can be administered in therapeutically effective amounts toprovide a SVR (for example, SVR12 or SVR24) after the completion of thetreatment. The patients may be treatment naïve patients or treatmentexperienced patients. The treatment duration can be no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks.

In some embodiments, the present invention features methods for treatingpatients with HCV genotype 2 infection. The methods compriseadministering to such a patient a combination of at least 2 DAAs for nomore than 12 weeks (e.g., the duration being 12 weeks), such as no morethan 8 weeks (e.g., the duration being 8 weeks), wherein the treatmentdoes not include administration of either interferon or ribavirin, andsaid at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 andCompound 2 can be administered in therapeutically effective amounts toprovide a SVR (for example, SVR12 or SVR24) after the completion of thetreatment. The patients may be treatment naïve patients or treatmentexperienced patients. The treatment duration can be no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks.

In some embodiments, the present invention features methods for treatingpatients with HCV genotype 3 infection. The methods compriseadministering to such a patient a combination of at least 2 DAAs for nomore than 12 weeks (e.g., the duration being 12 weeks), such as no morethan 8 weeks (e.g., the duration being 8 weeks), wherein the treatmentdoes not include administration of either interferon or ribavirin, andsaid at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 andCompound 2 can be administered in therapeutically effective amounts toprovide a SVR (for example, SVR12 or SVR24) after the completion of thetreatment. The patients may be treatment naïve patients or treatmentexperienced patients. The treatment duration can be no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks.

In some embodiments, the present invention features methods for treatingpatients with HCV genotype 4 infection. The methods compriseadministering to such a patient a combination of at least 2 DAAs for nomore than 12 weeks (e.g., the duration being 12 weeks), such as no morethan 8 weeks (e.g., the duration being 8 weeks), wherein the treatmentdoes not include administration of either interferon or ribavirin, andsaid at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 andCompound 2 can be administered in therapeutically effective amounts toprovide a SVR (for example, SVR12 or SVR24) after the completion of thetreatment. The patients may be treatment naïve patients or treatmentexperienced patients. The treatment duration can be no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks.

In some embodiments, the present invention features methods for treatingpatients with HCV genotype 5 infection. The methods compriseadministering to such a patient a combination of at least 2 DAAs for nomore than 12 weeks (e.g., the duration being 12 weeks), such as no morethan 8 weeks (e.g., the duration being 8 weeks), wherein the treatmentdoes not include administration of either interferon or ribavirin, andsaid at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 andCompound 2 can be administered in therapeutically effective amounts toprovide a SVR (for example, SVR12 or SVR24) after the completion of thetreatment. The patients may be treatment naïve patients or treatmentexperienced patients. The treatment duration can be no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks.

In some embodiments, the present invention features methods for treatingpatients with HCV genotype 6 infection. The methods compriseadministering to such a patient a combination of at least 2 DAAs for nomore than 12 weeks (e.g., the duration being 12 weeks), such as no morethan 8 weeks (e.g., the duration being 8 weeks), wherein the treatmentdoes not include administration of either interferon or ribavirin, andsaid at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 andCompound 2 can be administered in therapeutically effective amounts toprovide a SVR (for example, SVR12 or SVR24) after the completion of thetreatment. The patients may be treatment naïve patients or treatmentexperienced patients. The treatment duration can be no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks.

In any method, aspect, embodiment, example and preference describedherein, where at least two DAAs comprise Compound 1 and Compound 2, saidat least two DAAs preferably consist of Compound 1 and Compound 2.Preferably, Compound 1 is the compound of Example 3 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 5 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 6 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 7 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 1 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isselected from Table 3. Also preferably, Compound 1 is selected fromTable 4.

In any method, aspect, embodiment, example and preference describedherein, where at least two DAAs comprise Compound 1 and Compound 2, saidat least two DAAs preferably consist of Compound 1, Compound 2 and athird DAA. Preferably, Compound 1 is the compound of Example 3 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 6 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 7 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 41 or a pharmaceutically acceptable saltthereof. Also preferably, Compound 1 is the compound of Example 1 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isselected from Table 3. Also preferably, Compound 1 is selected fromTable 4.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the disease undergoingtherapy.

In any method described herein, Compound 1 and Compound 2 may beco-formulated in a single dosage form. Non-limiting examples of suitabledosage forms include liquid or solid dosage forms. Preferably, Compound1 and Compound 2 are formulated in a single solid dosage form in whichat least one of the DAAs is in an amorphous form, or highly preferablymolecularly dispersed, in a matrix which comprises a pharmaceuticallyacceptable water-soluble polymer and a pharmaceutically acceptablesurfactant. The other DAAs can also be in an amorphous form ormolecularly dispersed in the matrix, or formulated in different form(s)(e.g., in a crystalline form). More preferably, each of the two DAAs isin an amorphous form, or highly preferably molecularly dispersed, in amatrix which comprises a pharmaceutically acceptable water-solublepolymer and a pharmaceutically acceptable surfactant. Preferably,Compound 1 is the compound of Example 3 or a pharmaceutically acceptablesalt thereof. Also preferably, Compound 1 is the compound of Example 6or a pharmaceutically acceptable salt thereof. Also preferably, Compound1 is the compound of Example 41 or a pharmaceutically acceptable saltthereof. Also preferably, Compound 1 is the compound of Example 5 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 7 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 1 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isselected from Table 3. Also preferably, Compound 1 is selected fromTable 4.

In any method described herein, the patient being treated can be atreatment-naïve patient. Preferably, Compound 1 is the compound ofExample 3 or a pharmaceutically acceptable salt thereof. Alsopreferably, Compound 1 is the compound of Example 6 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 5 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 41 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 7 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 1 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isselected from Table 3. Also preferably, Compound 1 is selected fromTable 4.

In any method described herein, the patient being treated can be aninterferon non-responder. Preferably, Compound 1 is the compound ofExample 3 or a pharmaceutically acceptable salt thereof. Alsopreferably, Compound 1 is the compound of Example 5 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 6 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 7 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 41 or a pharmaceutically acceptable saltthereof. Also preferably, Compound 1 is the compound of Example 1 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isselected from Table 3. Also preferably, Compound 1 is selected fromTable 4.

In any method described herein, the patient being treated can be aninterferon null-responder. Preferably, Compound 1 is the compound ofExample 3 or a pharmaceutically acceptable salt thereof. Alsopreferably, Compound 1 is the compound of Example 5 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 6 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 7 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 41 or a pharmaceutically acceptable saltthereof. Also preferably, Compound 1 is the compound of Example 1 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isselected from Table 3. Also preferably, Compound 1 is selected fromTable 4.

In any method described herein, the patient being treated can be withoutcirrhosis. Preferably, Compound 1 is the compound of Example 3 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 5 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 6 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 7 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 41 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 1 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is selected from Table 3. Also preferably,Compound 1 is selected from Table 4.

In any method described herein, the patient being treated can be acirrhotic patient. Preferably, Compound 1 is the compound of Example 3or a pharmaceutically acceptable salt thereof. Also preferably, Compound1 is the compound of Example 5 or a pharmaceutically acceptable saltthereof. Also preferably, Compound 1 is the compound of Example 6 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 7 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 41 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 1 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is selected from Table 3. Also preferably,Compound 1 is selected from Table 4.

In any method described herein, the patient being treated can be apatient with compensated cirrhosis. Preferably, Compound 1 is thecompound of Example 3 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 5 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 6 or a pharmaceutically acceptable salt thereof.Also preferably, Compound 1 is the compound of Example 7 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isthe compound of Example 41 or a pharmaceutically acceptable saltthereof. Also preferably, Compound 1 is the compound of Example 1 or apharmaceutically acceptable salt thereof. Also preferably, Compound 1 isselected from Table 3. Also preferably, Compound 1 is selected fromTable 4.

In any method, aspect, embodiment, example and preference describedherein, Compound 1 preferably is the compound of Example 3 or apharmaceutically acceptable salt thereof.

In any method, aspect, embodiment, example and preference describedherein, Compound 1 preferably is the compound of Example 5 or apharmaceutically acceptable salt thereof.

In any method, aspect, embodiment, example and preference describedherein, Compound 1 preferably is the compound of Example 6 or apharmaceutically acceptable salt thereof.

In any method, aspect, embodiment, example and preference describedherein, Compound 1 preferably is the compound of Example 7 or apharmaceutically acceptable salt thereof.

In any method, aspect, embodiment, example and preference describedherein, Compound 1 preferably is the compound of Example 41 or apharmaceutically acceptable salt thereof.

In any method, aspect, embodiment, example and preference describedherein, Compound 1 preferably is selected from Table 3

In any method, aspect, embodiment, example and preference describedherein, Compound 1 preferably is selected from Table 4.

In any method, aspect, embodiment, example and preference describedherein, Compound 1 preferably is the compound of Example 1 or apharmaceutically acceptable salt thereof.

Any compound of Formula VII, VIII, IX, A, A′, A″ and B as describedherein, or any like phosphoramidate prodrug of Formula III′, can beprepared by reacting

with

(hereinafter “phosphoramidate prodrug moiety compound”), wherein X, R₁,R₂, R₃, R₄ and R₅ are as defined in Table 1, wherein R₁₀ and R₁₁ areeach independently C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and Ar isphenyl or naphthyl, and LG is a leaving group which can be selected, forexample but not limited to, from one of the following moieties:

LG can also be another suitable leaving group.

Any compound of Formula VII and VIII as described herein can be preparedby reacting

wherein X, R₁, R₂, R₃, R₄ and R₅ are as defined in Table 1, and Ar isphenyl, and LG is a leaving group which can be selected, for example butnot limited to, from one of the following moieties:

LG can also be another suitable leaving group.

Any compound of Formula VII, VIII, IX, A, A′, A″ and B as describedherein, or any like phosphoramidate prodrug of Formula III′, can beprepared by reacting

with

wherein X, R₁, R₂, R₃, R₄ and R₅ are as defined in Table 1, wherein R₁₀and R₁₁ are each independently C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl,and Ar is phenyl or naphthyl, and LG is a leaving group which can beselected, for example but not limited to, from one of the followingmoieties:

LG can also be another suitable leaving group.

Any compound of Formula VII and VIII as described herein can be preparedby reacting

wherein X, R₁, R₂, R₃, R₄ and R₅ are as defined in Table 1, and Ar isphenyl, and LG is a leaving group which can be selected, for example butnot limited to, from one of the following moieties:

LG can also be another suitable leaving group.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 113 nM. When tested against HCV genotype1b-Con1, the same compound showed an EC₅₀ value of 140 nM. Thetherapeutic index (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77replicon cells, was over 284-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 390 nM. When tested against HCV genotype1b-Con1, the same compound showed an EC₅₀ value of 368 nM. Thetherapeutic index (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77replicon cells, was over 256-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 56 nM. When tested against HCV genotype 1b-Con1,the same compound showed an EC₅₀ value of about 87 nM. The therapeuticindex (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77 repliconcells, was over 576-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of about 3000 nM. When tested against HCV genotype1b-Con1, the same compound showed an EC₅₀ value of about 2500 nM. Thetherapeutic index (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77replicon cells, was 9-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 141 nM. When tested against HCV genotype1b-Con1, the same compound showed an EC₅₀ value of 158 nM. Thetherapeutic index (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77replicon cells, was 709-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 106 nM. When tested against HCV genotype1b-Con1, the same compound showed an EC₅₀ value of 139 nM. Thetherapeutic index (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77replicon cells, was about 360-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 181 nM. When tested against HCV genotype1b-Con1, the same compound showed an EC₅₀ value of 226 nM. Thetherapeutic index (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77replicon cells, was 551-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 98 nM. When tested against HCV genotype 1b-Con1,the same compound showed an EC₅₀ value of 127 nM. The therapeutic index(TD₅₀/EC₅₀) of this compound, as measured in 1a-H77 replicon cells, wasover 149-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 13 nM. When tested against HCV genotype 1b-Con1,the same compound showed an EC₅₀ value of 29 nM. The therapeutic index(TD₅₀/EC₅₀) of this compound, as measured in 1a-H77 replicon cells, wasabout 2049-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 1200 nM. When tested against HCV genotype1b-Con1, the same compound showed an EC₅₀ value of 977 nM. Thetherapeutic index (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77replicon cells, was over 82-fold.

When tested against HCV genotype 1a-H77,

showed an EC₅₀ value of 480 nM. When tested against HCV genotype1b-Con1, the same compound showed an EC₅₀ value of 522 nM. Thetherapeutic index (TD₅₀/EC₅₀) of this compound, as measured in 1a-H77replicon cells, was over 245-fold.

It should be understood that the above-described embodiments and thefollowing examples are given by way of illustration, not limitation.Various changes and modifications within the scope of the presentinvention will become apparent to those skilled in the art from thepresent description.

Example 1. (S)-isopropyl2-(((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Example 1A. (4S,5R)-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one

A 500 mL round-bottomed flask was charged with 2-deoxy-D-ribose (10 g,74.6 mmol) and water (60 mL), followed by the dropwise addition ofbromine (59.6 g, 373 mmol). The contents were then stirred at roomtemperature for 5 days. The reaction mixture was then diluted with water(300 mL) and then extracted with tert-butyl methyl ether (3×200 mL). Theaqueous layer was then neutralized with the addition of silver carbonateuntil the pH of the aqueous solution reached 6. The resulting solidswere removed by filtration and the filtrate was concentrated undervacuum to provide a residue which was dissolved in ethyl acetate (200mL), followed by the addition of magnesium sulfate. After sittingovernight, the solids were filtered off and the filtrate wasconcentrated to provide the title compound as an oil (7.72 g, 78%). ¹HNMR (400 MHz, CDCl₃) δ 1.83 (t, J=5.9 Hz, 1H), 2.13 (d, J=4.3 Hz, 1H),2.57 (dd, J=18.1, 4.0 Hz, 1H), 3.00 (dd, J=18.0, 7.2 Hz, 1H), 3.85 (m,1H), 3.97 (m, 1H), 4.46 (q, J=3.2 Hz, 1H), 4.65 (m, 1H).

Example 1B.(4S,5R)-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

A 250 mL round-bottomed flask was charged with the product of Example 1A(7.5 g, 56.8 mmol) and N,N-dimethylformamide (50 mL), followed by theaddition of triisopropylsilyl chloride (30.1 mL, 142 mmol) and4-(dimethylamino)pyridine (0.35 g, 2.84 mmol). The contents were thenstirred at room temperature for 16 hrs. To the reaction mixture was thenadded a solution of aqueous hydrochloric acid (0.5 N, 300 mL) followedby extraction with ethyl acetate (3×200 mL). The combined organicextracts were dried over magnesium sulfate, and filtered. The filtratewas then concentrated and the residue purified by column chromatographyusing a 220 g silica gel column, eluting with 0-25% ethyl acetate inheptanes to provide 21.8 g (86%) of the title compound. ¹H NMR (400 MHz,CDCl₃) δ 1.04 (m, 42H), 2.47 (dd, J=17.6, 2.0 Hz, 1H), 2.92 (dd, J=17.6,6.6 Hz, 1H), 3.91 (dd, J=11.4, 2.4 Hz, 1H), 3.96 (dd, J=11.3, 3.0 Hz,1H), 4.44 (m, 1H), 4.69 (m, 1H).

Example 1C.(4R,5R)-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

Dry(4R,5S)-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one(Example 1B) (1.54 g, 3.46 mmol) was azeotroped with toluene (2×20 mL)and concentrated to dryness. The dry material was then dissolved indichloromethane (20 mL) followed by addition of triethylamine (2.90 mL,20.77 mmol) and cooled to 0° C. Trimethylsilyltrifluoromethanesulfonate(1.877 ml, 10.39 mmol) was added dropwise and allowed to stir for 30 minat 0° C. 2-chloro-1,3-bis(methoxycarbonyl)guanidine (Palau'Chlor) (0.878g, 3.98 mmol) was dissolved in 12 mL of dichloromethane and added viasyringe dropwise over 15 min resulting in a pale yellow solution.Gradually the reaction developed a darker yellow color over 15-20 min.Thin layer chromatography visualization (PMA+) after 90 min in 5% ethylacetate/heptanes showed most starting material was consumed with twospots nearly co-eluting which likely are corresponding chloro anomers.Saturated sodium bicarbonate solution was added and diluted with ethylacetate with stirring. Filtered off undissolved solid washing well withethyl acetate. Filtrate separated, washed with brine, dried overmagnesium sulfate, filtered and concentrated. The residue was furtherdiluted a second time with 1:1 dichloromethane/heptanes and filtered theundissolved material washing with same solvent mixture and concentratingfiltrate to give a yellow-orange oil. Material was purified on a 80 gsilica gel column eluting with 0-10% ethyl acetate in heptanes. Thedesired product was collected which exhibited a weak UV signature (254nM) as a broad peak around 20 min (0.89 g, 53.6%). MS (DCI (+) m/e 496(M+NH₄).

Example 1D.(3R,4R,5R)-3-bromo-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

Dry(4R,5R)-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (1.49 g, 3.11 mmol) (Example 1C) was dissolved indry tetrahydrofuran (10 ml, 0.3M)) followed by addition ofN-bromosuccinimide (0.968 g, 5.44 mmol) and cooled to −78° C. resultingin a suspension. Lithium bis(trimethylsilyl) amide (5.44 mL, 5.44 mmol,1M) was then added dropwise via syringe over 10 min yielding a thickyellow solution. The resultant mixture was kept at −78° C. for 45minutes and was still turbid albeit more free flowing. Thin layerchromatography aliquot was quenched with methanol and showed a higherR_(f) product from that of starting chloroketone with starting materialconsumed. Thin layer chromatography in 10% ethyl acetate/heptanes wasvisualized with PMA stain. Let reaction go for 1 hour then quenched with1 ml of methanol followed by addition of saturated ammonium chloride andallowed to warm to room temp and extracted with ethyl acetate threetimes, washed with brine, back extracted aqueous layer with ethylacetate and pooled organics, and dried over magnesium sulfate, filteredand concentrated. Dissolved residue in dichloromethane and loaded onto a40 g silica gel column eluting with 0-10% ethyl acetate/heptanes. Thedesired product was collected and concentrated to give a lite yellowviscous oil (1.64 g, 2.64 mmol, 85%). ¹H NMR (400 MHz, CDCl₃) δ 4.75 (d,J=7.6 Hz, 1H), 4.24-4.10 (m, 2H), 3.99 (dd, J=12.5, 1.9 Hz, 1H),1.32-0.97 (m, 42H). MS (DCI (+) m/e 576 (M+NH₄).

Example 1E.(3R,4R,5R)-3-bromo-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-ol

Dry(3R,4R,5R)-3-bromo-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (1.64 g, 2.94 mmol) (Example 1D) wasdissolved in toluene (25 ml) under N₂ and cooled to −78° C.Diisopropylaluminumhydride in toluene (23.51 ml, 23.51 mmol, 1M) addedvia syringe slowly and reaction was stirred for 1 h and was done afterthis time by thin layer chromatography 5% ethyl acetate in heptanesvisualized with PMA+ stain to give a more polar spot as major withseveral minor spots which were faint with PMA stain. The reaction wasthen quenched at −78° C. with saturated Rochelle's Salt and then allowedto warm slowly to ambient temperature and added ethyl acetate to givebiphasic turbid mixture which was stirred overnight. After stirringovernight reaction was now a clear biphasic mixture which wastransferred to separatory funnel and the organic layer separated.Aqueous phase was extracted two times with ethyl acetate, and combinedorganics where dried over magnesium sulfate, filtered and concentratedand dried to give a lite yellow oil as the desired product (1.65 g, 2.95mmol, 95% yield). NMR shows anomer mixture as expected but was notpurified further. MS (DCI (+) m/e 578 (M+NH₄).

Example 1F.(3R,4R,5R)-3-bromo-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl methanesulfonate

Dry(3R,4R,5R)-3-bromo-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-ol (0.730 g, 1.303 mmol) (Example 1E) wasdissolved in dichloromethane (15 mL) followed by addition oftriethylamine (0.636 mL, 4.56 mmol) and cooled to 0° C. Methanesulfonylchloride (0.256 mL, 3.26 mmol) was added dropwise via syringe and afterstirring for 20 min at 0° C. the reaction was warmed to ambienttemperature overnight. Reaction after this time was a turbidyellow/orange. Diluted with ethyl acetate and washed with 1N HCl,followed by saturated sodium bicarbonate, and brine. Dried overmagnesium sulfate, filtered and concentrated to give a yellow oil as thedesired product (0.825 g, 1.293 mmol, 99% yield) as a brownish yellowoil. as a mixture of mesylate anomers which was used as is withoutfurther purification.

Example 1G.N-(1-((2R,3R,4R,5R)-3-bromo-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide

N-(2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (1.902 g, 8.84 mmol) wassuspended in dichloroethane (20 mL) in a dry round bottom flask undernitrogen atmosphere followed by addition ofN,O-bis(trimethylsilyl)acetamide (2.397 g, 11.78 mmol) and heated toreflux for 2 h yielding a homogeneous solution. Cooled after heating toambient temperature. Dry(3R,4R,5R)-3-bromo-3-chloro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-ylmethanesulfonate (1.88 g, 2.95 mmol), (Example 1F) was dissolved indichloroethane (20 mL) and added to above solution after cooling to 0°C. and under nitrogen. Tin tetrachloride (1.535 g, 5.89 mmol) was thenadded dropwise to above cooled solution. After addition the reaction waswarmed to ambient temperature followed by heating at 70° C. for 16 hresulting in a dark brown solution. Thin layer chromatography in 30%ethyl acetate/heptanes visualized at 254 nM shows ˜1:2 ratio ofalpha/beta anomers. Added saturated sodium bicarbonate (15 ml) to give aturbid mixture. Diluted with ethyl acetate and filtered through a celiteplug washing well with ethyl acetate. Filtrate transferred to aseparatory funnel and washed again with saturated sodium bicarbonatesolution, brine and organics dried over magnesium sulfate, filtered andconcentrated. Dissolved residue in dichloromethane and loaded onto a 120g silica gel column eluting with 0-40% ethyl acetate in heptanes.Observed chromatographic peak ratio of about 1:2 for alpha, beta anomersrespectively which were separated to give the beta anomer as a whitesolid, (0.570 g, 25.6%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.52-11.26 (m,1H), 8.24 (d, J=7.7 Hz, 1H), 7.98 (d, 2H), 7.62 (t, J=7.3 Hz, 1H), 7.50(t, J=7.7 Hz, 2H), 7.39 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 4.33 (d, 1H),4.20 (d, J=12.4 Hz, 1H), 3.98 (dd, J=20.0, 10.4 Hz, 2H), 1.25-0.98 (m,42H). MS (ESI (+) m/e 758 (M+1).

Example 1H.1-((2R,3R,4R,5R)-3-bromo-3-chloro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione

A 50 mL round-bottomed flask was charged with the product of Example 1G(560 mg, 0.739 mmol) and acetic acid (8.47 mL, 148 mmol), followed bywater (1.33 mL, 74 mmol) were added and then the flask was heated at110° C. for 14 hrs. After cooling to room temperature, the solution wasconcentrated to an oil and then triturated with toluene two times andthen the residue used directly in the next reaction. The material wasthen dissolved in methanol (20 mL) and then ammonium fluoride (226 mg,6.11 mmol) added and the mixture heated at 60° C. for 17 hrs. Aftercooling to room temperature, the reaction mixture was then was thenconcentrated and the residue purified by column chromatography using asilica gel column, eluting with 0-25% methanol in dichloromethane toprovide 77 mg (37%) of the crude title compound. The material was thenpurified again using supercritical fluid chromatography (SFC) on achiral column. Preparative SFC was performed on a THAR/Waters SFC 80system running under SuperChrom software control. The preparative SFCwas equipped with a 8-way column switcher, CO2 pump, modifier pump,automated back pressure regulator (ABPR), UV detector, and 6-positionfraction collector. The mobile phase comprised of supercritical CO2supplied by a dewar of bone-dry non-certified CO2 pressurized to 350 psiwith a modifier of methanol at a flow rate of 70 g/min. The column wasat ambient temperature and the backpressure regulator was set tomaintain 100 bar. The sample was dissolved in methanol at aconcentration of 19.25 mg/mL and was loaded into the modifier stream in100 μL (˜2 mg) injections. The mobile phase was held isocratically at20% methanol:CO2. Fraction collection was time triggered. The instrumentwas fitted with a ChiralCel OJ-H column with dimensions 21 mm I.D.×250mm length with 5 μm particles. The retention time of the desiredcompound was from 2.05-2.30 minutes. This provided 41 mg of the titleproduct in 97% purity. ¹H NMR (400 MHz, DMSO-d6) δ 3.63 (m, 1H), 3.79(m, 2H), 4.02 (d, J=8.7 Hz, 1H), 5.48 (s, 1H), 5.69 (d, J=8.2 Hz, 1H),6.60 (s, 1H), 6.83 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 11.53 (s, 1H). MSESI− m/z 341 (M−H)+.

Example 1I. (S)-isopropyl2-(((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

The product of Example 1H and the corresponding phosphoramidate prodrugmoiety compound were mixed in a reaction flask. The contents were thenstirred at room temperature for 3 hrs. The reaction mixture wasextracted, and the combined organic extracts were dried and filtered.The filtrate was then concentrated and the residue purified by columnchromatography using a silica gel column, eluting with 0-100% ethylacetate in heptanes followed by a second column chromatography using asilica gel column, eluting with 0-5% methanol in dichloromethane toprovide 41 mg (60%) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ1.14 (d, J=6.3 Hz, 6H), 1.21 (d, J=7.1 Hz, 3H), 3.79 (m, 1H), 4.00 (m,1H), 4.08 (m, 1H), 4.30 (m, 2H), 4.84 (m, 1H), 5.56 (d, J=8.2 Hz, 1H),6.08 (dd, J=13.1, 10.1 Hz, 1H), 6.62 (s, 1H), 6.99 (d, J=5.5 Hz, 1H),7.20 (m, 3H), 7.36 (m, 2H), 7.63 (d, J=8.1 Hz, 1H), 11.58 (s, 1H). MSESI+ m/z 612 (M+H)+.

When tested against HCV genotype 1a-H77, the compound of Example 1showed an EC₅₀ value of 109 nM. When tested against HCV genotype1b-Con1, the compound of Example 1 showed an EC₅₀ value of 208 nM. Nocytotoxicity was observed during the study.

The therapeutic index (TD₅₀/EC₅₀) of the compound of Example 1, asmeasured in a toxicity study using 1a-H77 replicon cells, was about788-fold.

Example 2. (S)-isopropyl2-(((S)-(((2R,3R,4R,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Example 2A.(4R,5R)-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

To(4S,5R)-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one(5.466 g, 12.29 mmol) in tetrahydrofuran (THF) (40 mL) was addedN-fluorobenzenesulfonimide (5.0562 g, 16.03 mmol), cooled to −78° C. A 1M solution of lithium bis(trimethylsilyl)amide in toluene (13.5 mL,13.50 mmol) was added dropwise over 20 minutes. Stirred for another 20minutes. Quenched by dropwise addition of an aqueous solution of HCl (1N, 20 mL) at −78° C., removed the bath, and heptane (40 mL) and HCl (1N, 50 mL) were added. The mixture was stirred and warmed to roomtemperature. The layers were separated. The organic layer was washedwith HCl (1 N, 40 mL), water (20 mL) and brine (20 mL). The combinedaqueous layers were back-extracted with heptane (30 mL×2). The combinedorganic layers were dried (MgSO4) and concentrated. The residue waspurified by flash chromatography using a Biotage® SNAP 340 g silicacartridge eluted with a gradient of 0-60% dichloromethane/heptane andgave the title compound (4.31 g, 8.79 mmol, 71.6% yield). ¹H NMR (400MHz, Chloroform-d) δ ppm 1.04-1.12 (m, 84H), 3.94 (dd, J=12.2, 2.4 Hz,2H), 4.11 (dt, J=12.2, 2.1 Hz, 2H), 4.19 (dt, J=7.0, 2.3 Hz, 2H), 4.91(t, J=7.2 Hz, 1H), 4.96 (t, J=7.2 Hz, 1H), 5.07 (d, J=7.4 Hz, 1H), 5.20(d, J=7.4 Hz, 1H)

Example 2B.(3R,4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

Example 2C.(3S,4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

To a solution of the product of Example 2A (2.837 g, 6.13 mmol) intetrahydrofuran (THF) (30 mL) was added N-bromosuccinimide (1.637 g,9.20 mmol), cooled to −78° C. To the solution was added dropwise a 0.5 Msolution of potassium bis(trimethylsilyl)amide in toluene (25 mL, 12.50mmol) over 18 minutes. Stirred for 10 min. Quenched with an aqueoussolution of 1N HCl (15 mL) at −78° C., removed the bath, more HCl (1 N,35 mL) and heptane (50 mL) were added, warmed to room temperature. Thelayers were separated. The organic layer was washed with HCl (50 mL),water (30 mL), Na₂S₂O₃ (0.1 N, 50×2 mL) and brine (30 mL). The combinedaqueous layers were back-extracted with heptane (50 mL). The combinedorganic layers were dried (MgSO4) and concentrated. The residue waspurified by flash chromatography using a Biotage® SNAP 100 g silicacartridge eluted with a gradient of 0-5% ethyl acetate/heptane and gavethe title compound Example 2B containing small amount of Example 2C(2.09 g, 3.86 mmol, 62.9% yield). ¹H NMR (400 MHz, Chloroform-d) δ ppm0.98-1.11 (m, 89H), 3.97 (dd, J=12.5, 1.9 Hz, 1H), 4.05 (dt, J=7.7, 1.9Hz, 1H), 4.16 (dt, J=12.5, 2.3 Hz, 1H), 4.79 (dd, J=14.6, 7.7 Hz, 1H)

Example 2D.(3R,4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-ol

To a solution of the products of Examples 2B and 2C (2.09 g, 3.86 mmol)in toluene (12 mL) cooled to −78° C. was added dropwise a 1 M solutionof DIBAL-H (4.3 mL, 4.30 mmol) in toluene. The solution was stirred at−78° C. for 1.5 hours. Quenched the reaction with a 10% aqueous solutionof Rochelle's salt (20 mL) at −78° C., and the mixture was allowed towarm up. The mixture was filtered through a pad of Celite®, rinsed withmethyl t-butyl ether. The layers of the filtrate were separated. Theorganic layer was washed with 1 N HCl (20 mL×2), water (15 mL) and brine(15 mL). Dried (MgSO4), concentrated and purified by flashchromatography using a Biotage® SNAP 100 g silica cartridge eluted witha gradient of 0-30% dichloromethane/heptane and gave the title compound(1.8052 g, 3.32 mmol, 86% yield). ¹H NMR (501 MHz, Chloroform-d) δ ppm1.04-1.21 (m, 59H), 3.48 (d, J=12.7 Hz, 0.4H), 3.77-3.84 (m, 2H),3.86-3.91 (m, 2H), 3.94 (dt, J=6.6, 2.0 Hz, 1H), 4.08 (tdd, J=4.6, 3.5,1.0 Hz, 0.4H), 4.67 (ddd, J=11.6, 4.6, 0.9 Hz, 0.4H), 4.72 (dd, J=12.8,6.6 Hz, 1H), 5.17 (ddd, J=12.7, 5.9, 0.9 Hz, 0H), 5.34 (dd, J=9.2, 1.2Hz, 1H)

Example 2E.(3R,4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl benzoate

To a solution of the product of Example 2D (1.8052 g, 3.32 mmol) inpyridine (Py) (10 mL) was added N,N-dimethylpyridin-4-amine (0.041 g,0.332 mmol) followed by dropwise addition of benzoyl chloride (0.56 mL,4.82 mmol). The suspension was stirred at room temperature for 1 hour.The reaction mixture was concentrated at reduced pressure. The residuewas purified by flash chromatography using a Biotage® SNAP 100 g silicacartridge eluted with a gradient of 0-35% dichloromethane/heptane andgave the title compound (2.15 g, 3.32 mmol, 100% yield). ¹H NMR (400MHz, Chloroform-d) δ ppm 0.95-0.99 (m, 24H), 1.17 (t, J=5.7 Hz, 22H),3.86-3.95 (m, 2H), 4.03 (dt, J=11.9, 2.3 Hz, 1H), 4.84 (dd, J=12.3, 8.0Hz, 1H), 6.69 (d, J=1.5 Hz, 1H), 7.47 (d, J=7.7 Hz, 2H), 7.61 (t, J=7.5Hz, 1H), 8.02-8.06 (m, 2H)

Example 2F.(Z)—N-(1-((2R,3R,4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzimidicacid

To a suspension of (Z)—N-(2-hydroxypyrimidin-4-yl)benzimidic acid(1.0089 g, 4.69 mmol) in chlorobenzene (5.5 mL) was added(E)-trimethylsilyl N-(trimethylsilyl)acetimidate (1.2 mL, 4.89 mmol).Stirred at 80° C. for 45 minutes, and cooled to room temperature.

To the product of Example 2E (1 g, 1.544 mmol) was cannulated the abovesolution of bis-silylated cytosine. To the resulting solution was addedfreshly distilled (114-116° C., 760 mmHg) perchlorostannane (0.73 mL,6.22 mmol) at room temperature. The solution was stirred at 100° C.overnight. The reaction suspension was poured into an aqueous solutionof NaHCO₃ (1 N, 40 mL) at room temperature. The reaction flask wasrinsed with methyl t-butyl ether (15 mL) and added into the bicarbonatemixture. The mixture was stirred at room temperature for 1 hour,filtered through Celite®, rinsed with methyl t-butyl ether (50 mL). Thelayers of the filtrate were separated and the organic layer was washedwith water (20 mL), 1 N HCl (15 mL) and brine (15 mL). The filter cakeand the reaction flasks were rinsed with dichloromethane. The organiclayers were combined, dried (MgSO4) and concentrated to give a lightyellow oil, which was purified by flash chromatography using a RediSep®Rf gold 40 g silica cartridge eluted with a gradient of 0-25% ethylacetate/heptane and gave the title compound as a white solid (654.2 mg,0.883 mmol, 57.2% yield). ¹H NMR (501 MHz, DMSO-d₆) δ ppm 1.08 (dt,J=7.4, 2.1 Hz, 37H), 1.12-1.22 (m, 5H), 3.95-4.01 (m, 2H), 4.12-4.17 (m,1H), 4.48 (dd, J=15.6, 7.6 Hz, 1H), 6.65 (d, J=4.8 Hz, 1H), 7.41 (d,J=7.6 Hz, 1H), 7.50-7.55 (m, 2H), 7.64 (ddt, J=7.8, 6.9, 1.2 Hz, 1H),7.99-8.03 (m, 2H), 8.21 (d, J=7.6 Hz, 1H), 11.43 (s, 1H)); MS (APCI) m/z741.32 (M+H)⁺.

Example 2G.1-((2R,3R,4R,5R)-3-bromo-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione

To the product of Example 2F (86.8 mg, 0.117 mmol) was added acetic acid(AcOH) (0.6 mL) and water (0.15 mL). The suspension was stirred at 100°C. overnight. The solution was cooled to room temperature andconcentrated. The residue was azeotroped with toluene and dissolved inmethanol (MeOH) (0.3 mL). Ammonium fluoride (45.5 mg, 1.229 mmol) wasadded and the suspension was stirred at 60° C. overnight. Ammoniahydrofluoride (27 mg, 0.729 mmol) was added, stirred at 60° C. overnightand cooled to room temperature. The reaction mixture was diluted withdichloromethane, filtered and rinsed with 10% MeOH in dichloromethane.The filtrate was concentrated to a solid, which was purified by flashchromatography using a RediSep® Rf gold 12 g silica cartridge elutedwith a gradient of 0-10% MeOH/dichloromethane and gave the titlecompound (33 mg, 0.102 mmol, 87% yield) as a white gummy solid afterazeotroped with toluene. ¹H NMR (501 MHz, DMSO-d₆) δ ppm 3.63 (ddd,J=12.5, 5.4, 3.3 Hz, 1H), 3.73-3.81 (m, 2H), 4.07-4.17 (m, 1H), 5.33 (t,J=5.3 Hz, 1H), 5.70 (d, J=8.2 Hz, 1H), 6.39 (d, J=7.7 Hz, 1H), 6.67 (d,J=6.0 Hz, 1H), 7.89 (dd, J=8.2, 1.6 Hz, 1H), 11.55 (s, 1H); MS (APCI+)m/z 326.27 (M+H)⁺.

Example 2H. (S)-isopropyl2-(((S)-(((2R,3R,4R,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

The product of Example 2G (42.55 mg, 0.094 mmol) was reacted with thecorresponding phosphoramidate prodrug moiety compound. The resultingproduct was diluted with acetonitrile and purified on a reversed-phaseWaters HPLC using a Nova-Pak® HR C18, 6 μm, 60 Å, 40 mm×100 mm, PrepPakcartridge eluting with a gradient of 20-90% acetonitrile in aqueous 0.1%trifluoroacetic acid (60 mL/minute) to give the titled (12.88 mg, 0.020mmol, 43.4% yield). ¹H NMR (501 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.3 Hz,6H), 1.23 (dd, J=7.1, 0.9 Hz, 3H), 3.80 (td, J=10.2, 7.1 Hz, 1H), 4.02(dt, J=5.8, 2.8 Hz, 1H), 4.16-4.26 (m, 1H), 4.31 (ddd, J=11.9, 6.6, 2.9Hz, 1H), 4.86 (p, J=6.2 Hz, 1H), 5.61 (dd, J=8.2, 2.2 Hz, 1H), 6.07 (dd,J=13.1, 10.0 Hz, 1H), 6.41 (d, J=11.3 Hz, 1H), 6.83 (s, 1H), 7.18 (dd,J=7.3, 0.9 Hz, 1H), 7.21 (ddt, J=7.7, 2.3, 1.2 Hz, 2H), 7.35-7.40 (m,2H), 7.56 (dd, J=8.1, 2.3 Hz, 1H), 11.60 (d, J=2.2 Hz, 1H); MS (ESI−)m/z 591.9 (M−H)⁻.

Example 3. (S)-isopropyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Example 3A.(4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

The titled compound was prepared using the conditions described inExamples 2B and 2C. Using the product of Example 2A (5.8357 g, 12.61mmol) in tetrahydrofuran (THF) (55 mL), N-bromosuccinimide (2.69028 g,15.12 mmol) and lithium bis(trimethylsilyl)amide (15.5 mL, 15.50 mmol),the title compound was obtained as a mixture of the products of Examples2B and 2C in a ratio of 1/3.4 (5.9467 g, 9.88 mmol, 78% yield). ¹H NMR(400 MHz, Chloroform-d) δ ppm 1.04-1.21 (m, 58H), 3.94-4.12 (m, 3H),4.13-4.18 (m, 0.4H), 4.46 (ddd, J=6.4, 4.9, 2.5 Hz, 1H), 4.79 (dd,J=14.6, 7.7 Hz, 0.4H), 4.93 (dd, J=4.5, 2.8 Hz, 1H); MS (ESI+) m/z 541.0(M+H)⁺.

Example 3B.(3S,4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-ol

The titled compound was prepared using the conditions described inExample 2D. Using the product of Example 3A (6.0767 g, 11.22 mmol), thetitle compound was obtained as clean material (3.49 g, 6.42 mmol, 57.2%yield) and as a mixture containing the corresponding Br,F-diatereomers(2.8 g, 5.15 mmol, 45.9% yield). ¹H NMR (400 MHz, Chloroform-d) δ ppm1.06-1.14 (m, 84H), 3.58 (dd, J=12.1, 1.8 Hz, 1H), 3.82-3.86 (m, 2H),3.88-3.99 (m, 4H), 4.08 (dt, J=5.7, 2.3 Hz, 1H), 4.22 (dtd, J=5.9, 4.1,1.8 Hz, 1H), 4.75 (dd, J=6.0, 3.5 Hz, 1H), 4.87 (dd, J=16.1, 5.7 Hz,1H), 5.15 (dd, J=9.7, 5.5 Hz, 1H), 5.39 (dd, J=12.0, 2.1 Hz, 1H)

Example 3C.(3S,4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl benzoate

The titled compound was prepared using the conditions described inExample 2E. Using the product of Example 3B (3.66566 g, 6.74 mmol), thetitle compound was obtained as a colorless oil (4.0742 g, 6.29 mmol, 93%yield). ¹H NMR (501 MHz, Chloroform-d) δ ppm 1.06-1.31 (m, 67H), 3.86(dd, J=11.8, 2.4 Hz, 0.6H), 3.95-4.07 (m, 4H), 4.32 (qd, J=4.3, 1.0.6Hz, 1.2H), 4.87 (dd, J=4.2, 2.0 Hz, 1.2H), 4.96 (dd, J=19.6, 7.4 Hz,0.6H), 6.42 (d, J=9.5 Hz, 0.6H), 6.73 (s, 1H), 7.41-7.47 (m, 4H),7.56-7.61 (m, 2H), 8.02-8.05 (m, 1.2H), 8.08-8.11 (m, 2H)

Example 3D.(Z)—N-(1-((2R,3S,4R,5R)-3-bromo-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzimidicacid

The titled compound was prepared using the conditions described inExample 2F. Using the product of Example 3C (4.0742 g, 6.29 mmol),stirring at 106° C. overnight, the material containing the titlecompound was purified by flash chromatography using a RediSep® Rf 220 gsilica cartridge eluted with a gradient of 0-25% ethyl acetate/heptane.The resulting material was re-purified by flash chromatography using aRediSep® Rf gold 12 g silica cartridge eluted with a gradient of 0-25%ethyl acetate/dichloromethane and gave the title compound (230.38 mg,0.311 mmol, 4.94% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.99-1.26 (m, 42H), 3.98 (dd, J=12.2, 2.9 Hz, 1H), 4.05(d, J=8.5 Hz, 1H), 4.17 (dd, J=12.1, 2.4 Hz, 1H), 4.70 (dd, J=15.5, 8.2Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 7.41 (s, 1H), 7.52 (t, J=7.7 Hz, 4H),7.60-7.66 (m, 2H), 7.88-7.93 (m, 2H), 7.97-8.07 (m, 3H), 11.40 (s, 2H);MS (APCI+) m/z 741.36 (M+H)⁺.

Example 3E.1-((2R,3S,4R,5R)-3-bromo-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione

The titled compound was prepared using the conditions described inExample 2G. Using the product of Example 3D (230.38 mg, 0.311 mmol), thematerial containing the title compound was purified by flashchromatography using a RediSep® Rf gold 12 g silica cartridge elutedwith a gradient of 0-10% methanol (MeOH)/dichloromethane. The resultingmaterial was re-purified by flash chromatography using a RediSep® Rfgold 12 g silica cartridge eluted with a gradient of 0-40% ofacetonitrile (containing 10% MeOH) in dichloromethane and gave the titlecompound (59 mg, 0.172 mmol, 55.4% yield). ¹H NMR (501 MHz, DMSO-d₆) δppm 3.64 (ddd, J=12.6, 5.2, 3.0 Hz, 1H), 3.79-3.87 (m, 2H), 4.24-4.33(m, 1H), 5.35 (t, J=5.1 Hz, 1H), 5.73-5.76 (m, 1H), 6.24 (d, J=16.9 Hz,1H), 6.50 (d, J=7.1 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 11.57 (s, 1H); MS(DCI+) m/z 342.1 (M+NH₄)⁺.

Example 3F. (S)-isopropyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

The product of Example 3E (26 mg, 0.080 mmol) was reacted with thecorresponding phosphoramidate prodrug moiety compound. The resultingproduct was concentrated and then purified by flash chromatography usinga RediSep® Rf gold 12 g silica cartridge eluted with a gradient of0-100% ethyl acetate/dichloromethane. The resulting material wasre-purified by preparative thin layer chromatography eluted in 50%acetone/heptane and gave the title compound (31 mg, 0.050 mmol, 62.6%yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (d,J=2.2 Hz, 6H), 1.23 (dd, J=7.2, 1.0 Hz, 3H), 3.74-3.86 (m, 1H),4.00-4.05 (m, 1H), 4.22-4.40 (m, 2H), 4.86 (hept, J=6.3 Hz, 1H), 5.63(d, J=8.2 Hz, 1H), 6.06 (dd, J=13.0, 10.0 Hz, 1H), 6.23 (d, J=17.7 Hz,1H), 6.65 (d, J=7.1 Hz, 1H), 7.16-7.24 (m, 3H), 7.35-7.40 (m, 2H), 7.56(d, J=8.1 Hz, 1H), 11.58 (s, 1H); MS (ESI+) m/z 593.9 (M+H)⁺.

The compound of Example 3 had at least about 50-fold lower EC₅₀ (i.e.,was at least 50-fold more active) than the compound of Example 2 ingenotype 1a replicon assays, and had at least about 25-fold lower EC₅₀(i.e., at least 25-fold more active) than the compound of Example 2 ingenotype 1b replicon assays. The compound of Example 3 also showed muchless cytotoxicity in Huh-7 MTT assays. The compound of Example 3 wasalso shown to be more active (i.e., lower EC₅₀ values) than sofosbuvirin both genotype 1a and 1b replicon assays. In human hepatocyte wash-outexperiments (cells incubated for 4 hours with 100 μM of a compound ofinterest and then the active triphosphate was measured at 24 hours), thecompound of Example 3 had a similar intracellular triphosphateconcentration as sofosbuvir. In the dog pharmacokinetic liver biopsyexperiments (a single dose of 5 mg/kg of a compound of interest wasadministered to dogs, and the biopsy and measurement of theconcentration of the triphosphate active in the dog liver were done atboth 4 and 24 hours), the compound of Example 3 showed an intracellulartriphosphate concentration similar to or better than sofosbuvir.

Example 4. (S)-isopropyl2-(((S)-(((2R,3R,5R)-4,4-dibromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Example 4A. (4S,5R)-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one

A 500 mL round-bottomed flask was charged with 2-deoxy-D-ribose (10 g,74.6 mmol) and water (60 mL), followed by the dropwise addition ofbromine (59.6 g, 373 mmol). The contents were then stirred at roomtemperature for 5 days. The reaction mixture was then diluted with water(300 mL) and then extracted with tert-butyl methyl ether (3×200 mL). Theaqueous layer was then neutralized with the addition of silver carbonateuntil the pH of the aqueous solution reached 6. The resulting solidswere removed by filtration and the filtrate was concentrated undervacuum to provide a residue which was dissolved in ethyl acetate (200mL), followed by the addition of magnesium sulfate. After sittingovernight, the solids were filtered off and the filtrate wasconcentrated to provide the title compound as an oil (7.72 g, 78%). ¹HNMR (400 MHz, CDCl₃) δ 1.83 (t, J=5.9 Hz, 1H), 2.13 (d, J=4.3 Hz, 1H),2.57 (dd, J=18.1, 4.0 Hz, 1H), 3.00 (dd, J=18.0, 7.2 Hz, 1H), 3.85 (m,1H), 3.97 (m, 1H), 4.46 (q, J=3.2 Hz, 1H), 4.65 (m, 1H).

Example 4B.(4S,5R)-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

A 250 mL round-bottomed flask was charged with the product of Example 4A(7.5 g, 56.8 mmol) and N,N-dimethylformamide (50 mL), followed by theaddition of triisopropylsilyl chloride (30.1 mL, 142 mmol) and4-(dimethylamino)pyridine (0.35 g, 2.84 mmol). The contents were thenstirred at room temperature for 16 hrs. To the reaction mixture was thenadded a solution of aqueous hydrochloric acid (0.5 N, 300 mL) followedby extraction with ethyl acetate (3×200 mL). The combined organicextracts were dried over magnesium sulfate, and filtered. The filtratewas then concentrated and the residue purified by column chromatographyusing a 220 g silica gel column, eluting with 0-25% ethyl acetate inheptanes to provide 21.8 g (86%) of the title compound. ¹H NMR (400 MHz,CDCl₃) δ 1.04 (m, 42H), 2.47 (dd, J=17.6, 2.0 Hz, 1H), 2.92 (dd, J=17.6,6.6 Hz, 1H), 3.91 (dd, J=11.4, 2.4 Hz, 1H), 3.96 (dd, J=11.3, 3.0 Hz,1H), 4.44 (m, 1H), 4.69 (m, 1H).

Example 4C.(4R,5R)-3-bromo-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

(4R,5S)-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one(Example 4B) (5.0 g, 11.24 mmol) was azeotroped with toluene (2×20 mL)and concentrated to dryness. This material was then dissolved indichloromethane (50 mL) followed by addition of triethylamine (9.40 mL,67.4 mmol) and cooled to 0° C. Trimethylsilyltrifluoromethanesulfonate(6.09 ml, 33.7 mmol) was added dropwise and allowed to stir for 30 minat 0° C. N-Bromosuccinimide (NBS) (0.878 g, 3.98 mmol) was thendissolved in 50 mL of dichloromethane and added via syringe dropwiseover 5 min and then the resultant mixture was stirred at 0° C. for anadditional 90 minutes. A saturated aqueous sodium bicarbonate solutionwas then added and the mixture extracted with dichloromethane, thecombined organic extracts dried over magnesium sulfate, and filtered.The filtrate was then concentrated and the residue purified by columnchromatography using a 220 g silica gel column, eluting with 0-10% ethylacetate in heptanes to provide 1.98 g (34%) of the title compound. MS(ESI (+) m/e 540 (M+NH₄).

Example 4D.(4R,5R)-3,3-dibromo-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

Dry(4R,5R)-3-bromo-4-((triisopropylsiyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (1.85 g, 3.53 mmol) (Example 4C) was dissolved indry tetrahydrofuran (20 ml) followed by addition of1,2-dibromotetrachloroethane (1.73 g, 5.30 mmol) and cooled to −78° C.Lithium bis(trimethylsilyl) amide (5.30 mL, 5.30 mmol, 1M) was thenadded dropwise via syringe over 5 min yielding a colorless homogenoussolution. The mixture was kept at −78° C. for 60 minutes. Then quenchedwith 0.25 ml of acetic acid followed by addition of half saturatedaqueous saturated ammonium chloride and allowed to warm to room temp andextracted with ethyl acetate three times, washed with brine, backextracted aqueous layer with ethyl acetate and pooled organics, anddried over magnesium sulfate, filtered and concentrated. Then columnedthe residue with 0-5% ethyl acetate in heptanes. The desired product wascollected and concentrated to provide the desired product as a colorlessoil (1.45 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ 5.03 (d, J=7.2 Hz, 1H),4.22-4.18 (m, 2H), 3.98 (dd, J=13.3, 1.7 Hz, 1H), 1.32-1.08 (m, 42H). MS(ESI (+) m/e 620 (M+NH₄).

Example 4E.(4R,5R)-3,3-dibromo-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-ol

Dry(4R,5R)-3,3-dibromo-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (1.4 g, 2.32 mmol) (Example 4D) was dissolved intoluene (10 ml) under N₂ and cooled to −78° C.Diisopropylaluminumhydride in toluene (2.56 ml, 2.56 mmol, 1M) was addedvia syringe slowly over 2 minutes time and the mixture was stirred for30 minutes and was done after this time by thin layer chromatography.Then the reaction quenched at this temperature with saturated Rochelle'sSalt (15 mL of a 1.0 M aqueous solution) and then allowed to warm slowlyto ambient temperature and added heptane to give biphasic turbid mixturewhich was stirred overnight. After stirring overnight the reaction wasfiltered through celite and rinsed with ethyl acetate. Aqueous phase wasextracted two times with ethyl acetate, and combined organics wheredried over magnesium sulfate, filtered and concentrated then columnedthe residue with 0-10% ethyl acetate in heptanes to provide the desiredproduct (790 mg, 56%) as a colorless oil of lactol anomers. NMR showsanomer mixture as expected but was not purified further.

Example 4F.(4R,5R)-3,3-dibromo-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl benzoate

Dry(4R,5R)-3,3-dibromo-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-ol (0.780 g, 1.29 mmol) (Example 4E) was dissolved inpyridine (5 mL) and cooled to 0° C. followed by the addition of benzoylchloride (0.225 mL, 1.94 mmol) dropwise via syringe. After stirring thismixture for 2 hours at room temperature the reaction was diluted withethyl acetate and washed with half saturated aqueous ammonium chloride.The organic extract was then dried over magnesium sulfate, filtered andconcentrated then columned the residue with 0-10% ethyl acetate inheptanes to provide the desired product (840 mg, 92%) as a colorless oilof benzoate anomers. NMR shows anomer mixture as expected but was notpurified further. MS (ESI (+) m/e 726 (M+NH₄).

Example 4G.N-(1-((2R,4R,5R)-3,3-dibromo-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide

N-(2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (243 mg, 1.13 mmol) wassuspended in chlorobenzene (3 mL) in a dry round bottom flask undernitrogen atmosphere followed by addition ofN,O-bis(trimethylsilyl)acetamide (0.35 mL, 1.41 mmol) and heated at 80°C. for 45 minutes yielding a homogeneous solution. The mixture was thencooled after heating to ambient temperature. DryN-(1-((2R,4R,5R)-3,3-dibromo-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide(400 mg, 0.564 mmol), (Example 4F) was dissolved in chlorobenzene (3 mL)and added to the mixture followed by the addition of tin (IV) chloride(0.199 mL, 1.69 mmol) added dropwise. After addition the reaction washeated at 80° C. for 2 hours. Then added saturated sodium bicarbonate(10 ml) to give a turbid mixture. Diluted with ethyl acetate and stirredmixture for 30 minutes followed by filtration through a celite plugwashing well with ethyl acetate. Filtrate transferred to a separatoryfunnel and washed again with saturated sodium bicarbonate solution,brine and organics dried over magnesium sulfate, filtered andconcentrated. The residue was then columned eluting with 0-50% ethylacetate in heptanes. Observed chromatographic peak ratio of about 1:2for alpha, beta anomers respectively which were separated to give thebeta anomer as a colorless solid, (0.22 g, 49%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.42 (m, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.96 (d, 2H), 7.59 (m,1H), 7.48 (m, 2H), 7.36 (m, 1H), 6.83 (s, 1H), 4.45 (d, 1H), 4.19 (m,1H), 3.95 (m, 2H), 1.25-0.98 (m, 42H). MS (ESI (+) m/e 802 (M+H).

Example 4H.1-((2R,4R,5R)-3,3-dibromo-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione

A 25 mL round-bottomed flask was charged with the product of Example 4G(210 mg, 0.262 mmol) and acetic acid (3.0 mL, 52.4 mmol), followed bywater (0.944 mL, 52.4 mmol) were added and then the flask was heated at110° C. for 23 hrs. After cooling to room temperature, the solution wasconcentrated to an oil and then triturated with toluene two times andthen the residue used directly in the next reaction. The material wasthen dissolved in methanol (3 mL) and then ammonium fluoride (97 mg,2.62 mmol) added and the mixture heated at 60° C. for 21 hrs. Aftercooling to room temperature, the reaction mixture was then was thenconcentrated and the residue purified by column chromatography using asilica gel column, eluting with 0-10% methanol in dichloromethane toprovide 45 mg (46%) of the title compound as a colorless solid. ¹H NMR(400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.04 (d, J=8.6 Hz, 1H), 6.78 (s,1H), 6.60 (s, 1H), 5.68 (d, J=8.1 Hz, 1H), 5.45 (m, 1H), 4.15 (d, J=8.6Hz, 1H), 3.78 (m, 2H), 3.61 (m, 1H). MS ESI− m/z 385 (M−H)+.

Example 41. (S)-isopropyl2-(((S)-(((2R,3R,5R)-4,4-dibromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

The product of Example 4H (42 mg, 0.109 mmol) was reacted with thecorresponding phosphoramidate prodrug moiety compound. The resultingproduct was extracted with ethyl acetate (2×10 mL). The combined organicextracts were dried over magnesium sulfate, and filtered. The filtratewas then concentrated and the residue purified by column chromatographyusing a silica gel column, eluting with 0-100% ethyl acetate in heptanesto provide 46 mg (65%) of the title compound. ¹H NMR (400 MHz, DMSO-d6)δ 11.58 (s, 1H), 7.62 (d, J=5.9 Hz, 1H), 7.36 (m, 2H), 7.19 (m, 3H),6.95 (m, 1H), 6.63 (s, 1H), 6.07 (m, 1H), 5.56 (d, J=8.2 Hz, 1H), 4.83(m, 1H), 4.15 (m, 3H), 4.01 (m, 1H), 3.81 (m, 1H), 1.21 (d, J=7.1 Hz,3H), 1.14 (d, J=6.2 Hz, 6H). MS ESI− m/z 654 (M−H)+.

Example 5. Ethyl2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

A solution of the product from Example 1H (744 mg, 2.178 mmol) inanhydrous THF (10 ml), and DMPU (1 ml) was cooled to 0° C. A 1.0 Msolution of tert-butylmagnesium chloride in THF (2.396 ml, 2.396 mmol)was added dropwise, and the resulting mixture was stirred for 30 minbefore the corresponding phosphoramidate prodrug moiety compound wasadded in one portion. The reaction mixture was allowed to warm to roomtemperature and stirred for 12 hrs. The reaction was quenched with asaturated solution of NH₄Cl, and the mixture was extracted withdichloromethane (2×). The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo, and the product wasisolated by C18 HPLC using a solvent gradient of 5-95% acetonitrile inwater (0.1% TFA). The title compound was obtained as a colorless solid(0.82 g, 62%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.57 (d, J=2.3 Hz, 1H),7.70-7.54 (m, 1H), 7.40-7.32 (m, 2H), 7.23-7.12 (m, 3H), 7.01 (s, 1H),6.63 (s, 1H), 6.03-5.91 (m, 1H), 5.57-5.48 (m, 1H), 4.42-4.25 (m, 2H),4.13-3.97 (m, 4H), 1.40-1.30 (m, 6H), 1.15-1.09 (m, 3H).

Example 6. Ethyl2-(((R)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The product from Example 1C was purified by chiral SFC chromatographyusing a Chiralpak AD-H column, eluting with isocratic mobile phase thatconsisted of supercritical CO₂ and 40% methanol. The title compound wasthe first of two stereoisomers to elute. ¹H NMR (400 MHz, DMSO-d₆) δ11.56 (d, J=2.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.38-7.30 (m, 2H),7.22-7.17 (m, 2H), 7.13 (t, J=7.5 Hz, 1H), 7.03 (s, 1H), 6.61 (s, 1H),5.99 (d, J=9.7 Hz, 1H), 5.49 (dd, J=8.2, 2.2 Hz, 1H), 4.41-4.23 (m, 2H),4.07-3.95 (m, 4H), 1.37-1.34 (m, 3H), 1.30 (s, 3H), 1.11 (t, J=7.1 Hz,3H).

The compound of Example 6 showed an EC50 value of about 2-3 M ingenotype 1a replicon assay, and an EC₅₀ value of about 2-3 μM ingenotype 1b replicon assay. In human hepatocyte wash-out experiments(cells incubated for 4 hours with 100 μM of a compound of interest andthen the active triphosphate was measured at 24 hours), the compound ofExample 6 showed a significantly higher intracellular triphosphateconcentration than the compound of Example 1. In the dog pharmacokineticliver biopsy experiments (a single dose of 5 mg/kg of a compound ofinterest was administered to dogs, and the biopsy and measurement of theconcentration of the triphosphate active in the dog liver were done atboth 4 and 24 hours), the compound of Example 6 also showed asignificantly higher intracellular triphosphate concentration than thecompound of Example 1.

Example 7. Ethyl2-(((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The product from Example 1C was purified by chiral SFC chromatographyusing a Chiralpak AD-H column, eluting with isocratic mobile phase thatconsisted of supercritical CO₂ and 40% methanol. The title compound wasthe second of two stereoisomers to elute. ¹H NMR (501 MHz, DMSO-d₆) δ11.58 (d, J=2.2 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.36 (dd, J=8.6, 7.3Hz, 2H), 7.24-7.14 (m, 3H), 7.01 (s, 1H), 6.62 (s, 1H), 5.96 (d, J=9.6Hz, 1H), 5.52 (dd, J=8.2, 2.2 Hz, 1H), 4.40-4.25 (m, 2H), 4.14-3.97 (m,4H), 1.37 (s, 3H), 1.33 (s, 3H), 1.12 (t, J=7.1 Hz, 3H).

The compound of Example 7 showed an EC50 value of about 0.6 μM ingenotype 1a replicon assay, and an EC₅₀ value of about 1 μM in genotype1b replicon assay. In human hepatocyte wash-out experiments (cellsincubated for 4 hours with 100 μM of a compound of interest and then theactive triphosphate was measured at 24 hours), the compound of Example 7showed a significantly higher intracellular triphosphate concentrationthan the compound of Example 1. In the dog pharmacokinetic liver biopsyexperiments (a single dose of 5 mg/kg of a compound of interest wasadministered to dogs, and the biopsy and measurement of theconcentration of the triphosphate active in the dog liver were done atboth 4 and 24 hours), the compound of Example 7 also showed asignificantly higher intracellular triphosphate concentration than thecompound of Example 1.

Example 8. Ethyl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 7.62 (d, J=8.2Hz, 1H), 7.35 (ddd, J=9.3, 7.2, 2.1 Hz, 2H), 7.22-7.11 (m, 3H),7.08-6.93 (m, 1H), 6.64-6.58 (m, 1H), 6.17-6.03 (m, 1H), 5.58-5.51 (m,1H), 4.41-4.21 (m, 2H), 4.02 (qd, J=7.1, 2.1 Hz, 4H), 3.88-3.73 (m, 1H),1.23-1.09 (m, 6H).

Example 9. Ethyl((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

The product from Example 8 was purified by chiral SFC chromatographyusing a Chiralpak AD-H column, eluting with 35% methanol insupercritical CO₂ to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 11.55 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.40-7.31 (m, 2H),7.21-7.11 (m, 3H), 7.04 (s, 1H), 6.63 (s, 1H), 6.12 (dd, J=12.8, 9.9 Hz,1H), 5.55 (d, J=8.1 Hz, 1H), 4.38 (dd, J=12.0, 5.6 Hz, 1H), 4.33-4.23(m, 1H), 4.08-3.95 (m, 4H), 3.85-3.71 (m, 1H), 1.18 (dd, J=7.1, 1.2 Hz,3H), 1.11 (t, J=7.1 Hz, 3H).

Example 10. Ethyl((R)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

The product from Example 8 was purified by chiral SFC chromatographyusing a Chiralpak AD-H column, eluting with 35% methanol insupercritical CO₂ to provide the title compound. ¹H NMR (501 MHz,DMSO-d₆) δ 11.58 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.39-7.34 (m, 2H),7.23-7.15 (m, 3H), 6.99 (d, J=5.8 Hz, 1H), 6.62 (s, 1H), 6.10 (dd,J=13.0, 10.0 Hz, 1H), 5.56 (d, J=8.3 Hz, 1H), 4.37-4.24 (m, 2H),4.11-3.97 (m, 4H), 3.89-3.79 (m, 1H), 1.23 (dd, J=7.2, 0.9 Hz, 3H), 1.14(t, J=7.1 Hz, 3H).

Example 11. Isopropyl2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.60-11.55 (m, 1H),7.70-7.55 (m, 1H), 7.41-7.31 (m, 2H), 7.25-7.12 (m, 3H), 7.05-6.94 (m,1H), 6.66-6.59 (m, 1H), 5.98-5.85 (m, 1H), 5.55-5.47 (m, 1H), 4.88-4.77(m, 1H), 4.41-4.25 (m, 2H), 4.13-3.96 (m, 2H), 1.38-1.30 (m, 6H),1.16-1.10 (m, 6H).

Example 12. Isopropyl2-(((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The product from Example 11 was purified by chiral SFC chromatographyusing a Chiralcel OJ-H column, eluting with 30% isopropanol insupercritical CO₂ to provide the title compound. ¹H NMR (501 MHz,DMSO-d₆) δ 11.53 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.39-7.33 (m, 2H),7.24-7.19 (m, 2H), 7.17 (t, J=7.4 Hz, 1H), 6.99 (d, J=5.7 Hz, 1H), 6.62(s, 1H), 5.89 (d, J=9.6 Hz, 1H), 5.52 (d, J=8.2 Hz, 1H), 4.83 (hept,J=6.4 Hz, 1H), 4.41-4.26 (m, 2H), 4.14-3.97 (m, 2H), 1.36 (s, 3H), 1.32(s, 3H), 1.13 (t, J=6.4 Hz, 6H).

Example 13. Isopropyl2-(((R)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The product from Example 11 was purified by chiral SFC chromatographyusing a Chiralcel OJ-H column, eluting with 30% isopropanol insupercritical CO₂ to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 11.56 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.34 (dd, J=8.5, 7.3Hz, 2H), 7.23-7.17 (m, 2H), 7.17-7.09 (m, 1H), 7.03 (s, 1H), 6.62 (s,1H), 5.93 (d, J=9.6 Hz, 1H), 5.48 (d, J=8.1 Hz, 1H), 4.82 (hept, J=6.3Hz, 1H), 4.43-4.22 (m, 2H), 4.01 (s, 2H), 1.35-1.32 (m, 3H), 1.30 (s,3H), 1.12 (t, J=6.0 Hz, 6H).

Example 14. Isopropyl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.61-11.56 (m, 1H),7.71-7.54 (m, 1H), 7.36 (dd, J=8.6, 7.1 Hz, 2H), 7.26-7.13 (m, 3H),7.08-6.95 (m, 1H), 6.63 (s, 1H), 6.19-6.00 (m, 1H), 5.62-5.51 (m, 1H),4.89-4.77 (m, 1H), 4.42-4.24 (m, 1H), 4.14-3.96 (m, 2H), 3.82-3.70 (m,1H), 1.22-1.16 (m, 3H), 1.13 (dt, J=5.6, 2.7 Hz, 6H).

Example 15. Isopropyl((R)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate

The product from Example 14 was purified by chiral SFC chromatographyusing a Chiralpak AD-H column, eluting with 40% methanol insupercritical CO₂ to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 11.59 (d, J=2.3 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.43-7.33(m, 2H), 7.26-7.13 (m, 3H), 7.05 (s, 1H), 6.63 (s, 1H), 6.14 (dd,J=13.6, 10.1 Hz, 1H), 5.59 (dd, J=8.1, 2.2 Hz, 1H), 4.84 (hept, J=6.3Hz, 1H), 4.41-4.23 (m, 2H), 4.00 (s, 2H), 3.82-3.69 (m, 1H), 1.23-1.18(m, 3H), 1.13 (dd, J=6.3, 4.6 Hz, 6H).

Example 16. Isopropyl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(3-methoxyphenoxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (501 MHz, DMSO-d₆) δ 11.60-11.56 (m, 1H),7.70-7.60 (m, 1H), 7.28-7.21 (m, 1H), 7.10-6.94 (m, 1H), 6.81-6.72 (m,3H), 6.68-6.60 (m, 1H), 6.16-6.03 (m, 1H), 5.60-5.54 (m, 1H), 4.87-4.79(m, 1H), 4.42-4.23 (m, 2H), 4.13-3.96 (m, 2H), 3.84-3.66 (m, 4H),1.24-1.17 (m, 3H), 1.16-1.11 (m, 6H).

Example 17. Isopropyl((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(3-methoxyphenoxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d, J=2.2 Hz, 1H), 7.62(d, J=8.2 Hz, 1H), 7.28-7.19 (m, 1H), 6.98 (s, 1H), 6.80-6.70 (m, 3H),6.61 (s, 1H), 6.07 (dd, J=13.1, 10.0 Hz, 1H), 5.55 (dd, J=8.1, 2.2 Hz,1H), 4.82 (hept, J=6.3 Hz, 1H), 4.37-4.21 (m, 2H), 4.12-3.93 (m, 2H),3.85-3.71 (m, 1H), 3.71 (s, 3H), 1.20 (d, J=7.1 Hz, 3H), 1.12 (d, J=6.3Hz, 6H).

Example 18. Isopropyl((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (d, J=2.2 Hz, 1H),11.36 (s, 1H), 8.16-8.07 (m, 1H), 7.99-7.90 (m, 1H), 7.74 (dd, J=6.6,2.6 Hz, 1H), 7.62-7.52 (m, 2H), 7.52-7.41 (m, 2H), 6.99 (d, J=5.6 Hz,1H), 6.61 (s, 1H), 6.25 (dd, J=12.6, 10.0 Hz, 1H), 5.41 (dd, J=8.2, 2.1Hz, 1H), 4.90-4.79 (m, 1H), 4.45-4.30 (m, 2H), 4.17-3.97 (m, 2H),3.94-3.81 (m, 1H), 1.23 (d, J=7.1 Hz, 3H), 1.12 (dd, J=6.2, 1.4 Hz, 6H).

Example 19.(2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((S)—(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3-ylL-valinate

Example 19A.(2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((S)—(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3-yl(tert-butoxycarbonyl)-L-valinate

A mixture of Boc-L-Valine (0.427 g, 1.965 mmol), carbonyldiimidazole(0.319 g, 1.965 mmol) (0.319 g, 1.965 mmol), and triethylamine (0.685ml, 4.91 mmol) in anhydrous tetrahydrofuran (16 ml) was stirred at 50°C. under N₂ for 90 min. The resulting mixture was cooled to roomtemperature, and the product from Example 1I (1.00 g, 1.637 mmol) and4-dimethylaminopyridine (0.020 g, 0.164 mmol) were added. The resultingmixture was stirred at 60° C. overnight. The mixture was cooled to rtand partitioned between 1 N aq HCl and EtOAc (3×). The combined organiclayers were dried over sodium sulfate. The drying agent was filteredoff, and the solvent was removed in vacuo. The crude product waspurified by column chromatography on silica gel using a solvent gradientof 0-5% methanol in dichloromethane. The title compound was obtained acolorless solid (0.958 g, 72%).

Example 19B.(2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((S)—(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3-ylL-valinate

A solution of the product from Example 19A (0.565 g, 0.698 mmol) indichloromethane (4 ml) and trifluoroacetic acid (1 ml, 12.98 mmol) wasstirred at room temperature for 1 hr and then concentrated in vacuo. Theresidue was dissolved in ethyl acetate and washed with saturated aq.sodium bicarbonate. The layers were separated and the organic layer wasdried over sodium sulfate. The drying agent was filtered off, and thesolvent was removed in vacuo. The crude product was purified by columnchromatography on silica gel using a solvent gradient of 50-100% ethylacetate in heptanes. The title compound was obtained as a colorlesssolid (0.439 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J=8.2 Hz,1H), 7.34 (dd, J=8.6, 7.2 Hz, 2H), 7.23-7.10 (m, 2H), 6.61 (s, 1H), 6.07(dd, J=13.0, 10.0 Hz, 1H), 5.69-5.60 (m, 1H), 5.51 (s, 1H), 4.83 (hept,J=6.3 Hz, 1H), 4.27 (dtd, J=15.7, 7.4, 6.9, 4.5 Hz, 3H), 3.76 (tq,J=10.1, 7.1 Hz, 1H), 3.23 (d, J=5.7 Hz, 1H), 1.99-1.84 (m, 1H),1.23-1.17 (m, 3H), 1.12 (dd, J=6.2, 1.8 Hz, 6H), 0.90 (d, J=6.8 Hz, 3H),0.84 (d, J=6.8 Hz, 3H).

Example 20.(2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((S)—(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(naphthalen-1-yloxy)phosphoryl)oxy)methyl)tetrahydrofuran-3-ylL-valinate

The title compound was prepared using a method similar to that describedfor Example 19, substituting the product from Example 18 for the productfrom Example 1I. 1H NMR (400 MHz, DMSO-d6) d 11.53 (s, 1H), 8.12-8.07(m, 1H), 7.96-7.89 (m, 1H), 7.73 (dd, J=6.7, 2.6 Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.57-7.52 (m, 2H), 7.48-7.41 (m, 2H), 6.59 (s, 1H), 6.26 (dd,J=12.6, 9.9 Hz, 1H), 5.57-5.49 (m, 2H), 4.83 (hept, J=6.3 Hz, 1H),4.42-4.24 (m, 3H), 3.85 (tq, J=10.1, 7.1 Hz, 1H), 3.22 (d, J=5.7 Hz,1H), 1.89 (ddd, J=13.6, 6.9, 5.7 Hz, 1H), 1.22 (d, J=7.1 Hz, 3H), 1.11(d, J=6.3 Hz, 6H), 0.87 (d, J=6.7 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H).

Example 21.(2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((S)—(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3-ylL-alaninate

The title compound was prepared using the methods described for Example19, substituting Boc-L-Alanine for Boc-L-Valine. 1H NMR (400 MHz,DMSO-d6) δ 11.64 (d, J=2.2 Hz, 1H), 8.46 (br s, 2H), 7.73 (d, J=8.2 Hz,1H), 7.35 (dd, J=8.7, 7.2 Hz, 2H), 7.17 (dd, J=11.4, 7.8 Hz, 3H), 6.62(s, 1H), 6.09 (dd, J=13.0, 10.1 Hz, 1H), 5.68 (dd, J=8.2, 2.2 Hz, 1H),5.58 (br s, 1H), 4.83 (p, J=6.3 Hz, 1H), 4.32 (dqt, J=19.8, 7.6, 4.0 Hz,3H), 3.77 (tq, J=10.2, 7.1 Hz, 1H), 1.46 (d, J=7.2 Hz, 3H), 1.20 (d,J=7.0 Hz, 3H), 1.12 (d, J=6.3 Hz, 6H).

Example 22. Isopropyl((R)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5, followed by purification by chiral SFC chromatographyusing a Regis Whelk-O (S,S) column, eluting with 20% methanol insupercritical CO₂. ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (d, J=2.1 Hz, 1H),7.63 (d, J=8.2 Hz, 1H), 7.36 (dd, J=8.6, 7.2 Hz, 2H), 7.17 (d, J=8.3 Hz,3H), 7.05 (s, 1H), 6.64 (s, 1H), 6.12 (dd, J=12.9, 9.9 Hz, 1H), 5.57(dd, J=8.1, 2.2 Hz, 1H), 4.84 (hept, J=6.3 Hz, 1H), 4.39 (dd, J=12.1,5.7 Hz, 1H), 4.34-4.25 (m, 1H), 4.04 (s, 2H), 3.81-3.68 (m, 1H), 1.19(d, J=7.2 Hz, 3H), 1.13 (dd, J=6.3, 2.6 Hz, 6H).

Example 23. Isopropyl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(m-tolyloxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (d, J=1.9 Hz, 1H), 7.61(d, J=8.1 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.98 (dd, J=12.5, 6.3 Hz,3H), 6.64-6.57 (m, 1H), 6.12-5.97 (m, 1H), 5.54 (dd, J=8.1, 2.3 Hz, 1H),4.83 (hept, J=6.2 Hz, 1H), 4.37-4.20 (m, 2H), 4.12-3.93 (m, 2H),3.83-3.70 (m, 1H), 2.25 (s, 3H), 1.22-1.16 (m, 3H), 1.15-1.09 (m, 6H).

Example 24. Isopropyl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(4-fluorophenoxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 7.64 (d, J=8.3Hz, 1H), 7.28-7.15 (m, 3H), 7.09-6.94 (m, 1H), 6.67-6.59 (m, 1H),6.19-6.04 (m, 1H), 5.64-5.56 (m, 1H), 4.84 (hept, J=6.3 Hz, 1H),4.42-4.22 (m, 2H), 4.13-3.94 (m, 2H), 3.86-3.69 (m, 1H), 1.25-1.17 (m,3H), 1.13 (d, J=6.3 Hz, 6H).

Example 25. Isopropyl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(3-fluorophenoxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (500 MHz, DMSO-d₆) δ 11.62 (d, J=2.2 Hz, 1H), 7.66(d, J=8.1 Hz, 1H), 7.48-7.39 (m, 1H), 7.17-6.99 (m, 4H), 6.65 (s, 1H),6.22 (dd, J=13.1, 10.0 Hz, 1H), 5.62 (dd, J=8.2, 2.2 Hz, 1H), 4.86(hept, J=6.1 Hz, 1H), 4.42-4.27 (m, 2H), 4.16-3.98 (m, 2H), 3.90-3.76(m, 1H), 1.24 (d, J=7.1 Hz, 3H), 1.16 (d, J=6.2 Hz, 6H).

Example 26. Isopropyl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)glycinate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.60-11.55 (m, 1H),7.69-7.56 (m, 1H), 7.36 (t, J=7.8 Hz, 2H), 7.25-7.13 (m, 3H), 7.00 (s,1H), 6.63 (s, 1H), 6.07-5.91 (m, 1H), 5.62-5.52 (m, 1H), 4.88 (hept,J=6.5 Hz, 1H), 4.46-4.23 (m, 2H), 4.14-3.95 (m, 2H), 3.65-3.55 (m, 2H),1.19-1.10 (m, 6H).

Example 27. Sec-butyl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (d, J=2.2 Hz, 1H), 7.62(d, J=8.2 Hz, 1H), 7.34 (dd, J=8.6, 7.2 Hz, 2H), 7.23-7.11 (m, 3H), 6.97(s, 1H), 6.65-6.57 (m, 1H), 6.16-6.00 (m, 1H), 5.55 (dd, J=8.2, 2.2 Hz,1H), 4.68 (h, J=6.3 Hz, 1H), 4.40-4.21 (m, 2H), 4.12-3.93 (m, 2H),3.88-3.71 (m, 1H), 1.51-1.41 (m, 2H), 1.24-1.15 (m, 3H), 1.11-1.05 (m,3H), 0.78 (t, J=7.4 Hz, 3H).

Example 28. 1-methoxypropan-2-yl((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (501 MHz, DMSO-d₆) δ 11.60-11.56 (m, 1H),7.67-7.59 (m, 1H), 7.40-7.32 (m, 2H), 7.24-7.14 (m, 3H), 7.10-6.91 (m,1H), 6.66-6.60 (m, 1H), 6.19-6.06 (m, 1H), 5.60-5.54 (m, 1H), 4.96-4.86(m, 1H), 4.42-4.24 (m, 2H), 4.12-3.96 (m, 2H), 3.89-3.76 (m, 1H),3.33-3.28 (m, 1H), 3.23-3.21 (m, 3H), 1.25-1.18 (m, 3H), 1.11-1.08 (m,3H).

Example 29.(2S)-2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propylisobutyrate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.63-11.46 (m, 1H),7.67-7.56 (m, 1H), 7.40-7.30 (m, 2H), 7.23-7.10 (m, 3H), 7.00 (s, 1H),6.65-6.58 (m, 1H), 5.70-5.50 (m, 2H), 4.30 (dp, J=9.8, 5.7 Hz, 2H),4.13-3.95 (m, 2H), 3.89-3.73 (m, 2H), 2.49-2.38 (m, 1H), 1.02 (dd,J=7.0, 1.6 Hz, 9H).

Example 30.(2S)-2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propylpropionate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.59-11.55 (m, 1H),7.67-7.58 (m, 1H), 7.39-7.31 (m, 2H), 7.23-7.11 (m, 3H), 7.01 (s, 1H),6.64-6.59 (m, 1H), 5.66-5.50 (m, 2H), 4.38-4.23 (m, J=6.4 Hz, 2H),4.12-3.94 (m, 2H), 3.86-3.77 (m, 2H), 2.22 (qd, J=7.5, 1.4 Hz, 2H),1.03-0.98 (m, 3H), 0.95 (t, J=7.5 Hz, 3H).

Example 31.(2S)-2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propyl3-methoxy-2-methylpropanoate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (501 MHz, DMSO-d₆) δ 11.69-11.50 (m, 1H),7.69-7.59 (m, 1H), 7.37 (dd, J=8.7, 7.3 Hz, 2H), 7.24-7.13 (m, 3H),7.09-6.96 (m, 1H), 6.67-6.60 (m, 1H), 5.70-5.52 (m, 2H), 4.40-4.25 (m,2H), 4.14-3.97 (m, 2H), 3.93-3.76 (m, 2H), 3.46-3.39 (m, 2H), 3.18 (d,J=1.3 Hz, 3H), 2.68-2.58 (m, 1H), 1.06-0.98 (m, 6H).

Example 32.(2S)-2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propyl2-methoxyacetate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (501 MHz, DMSO-d₆) δ 11.67-11.48 (m, 1H),7.69-7.59 (m, 1H), 7.42-7.34 (m, 2H), 7.24-7.14 (m, 3H), 7.12-6.90 (m,1H), 6.66-6.60 (m, 1H), 5.70-5.51 (m, 2H), 4.41-4.26 (m, 2H), 4.12-3.99(m, 2H), 3.98-3.86 (m, 5H), 3.46-3.37 (m, 2H), 1.07-0.99 (m, 3H).

Example 33.(2S)-2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propylpivalate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 7.65 (d, J=8.2Hz, 1H), 7.41-7.33 (m, 2H), 7.25-7.13 (m, 3H), 7.02 (d, J=5.6 Hz, 1H),6.63 (s, 1H), 5.64 (dd, J=12.5, 9.8 Hz, 1H), 5.56 (dd, J=8.2, 2.2 Hz,1H), 4.32 (d, J=5.8 Hz, 2H), 4.14-3.97 (m, 2H), 3.87 (dd, J=10.7, 5.7Hz, 1H), 3.76 (dd, J=10.7, 6.4 Hz, 1H), 3.48-3.37 (m, 1H), 1.13-0.98 (m,12H).

Example 34.(2S)-2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propyl(methoxycarbonyl)-L-valinate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 7.66-7.59 (m,1H), 7.47 (d, J=8.6 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.24-7.14 (m, 3H),7.02 (s, 1H), 6.63 (s, 1H), 5.69-5.60 (m, 1H), 5.56 (dd, J=8.2, 2.2 Hz,1H), 4.37-4.27 (m, 2H), 4.13-3.99 (m, 2H), 3.98-3.88 (m, 2H), 3.81 (dd,J=10.7, 6.2 Hz, 1H), 3.53 (s, 3H), 2.08-1.96 (m, 1H), 1.04 (dd, J=6.7,3.9 Hz, 3H), 0.82 (dd, J=6.8, 3.1 Hz, 6H).

Example 35.(2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3-yl3-hydroxy-3-methylbutanoate

A mixture of the product from Example 1I (128 mg, 0.210 mmol),3-hydroxy-3-methylbutanoic acid (24.76 mg, 0.210 mmol),N,N-dimethylpyridin-4-amine (2.56 mg, 0.021 mmol) and EDCI (60.0 mg,0.314 mmol) in dichloromethane (2 ml) was stirred at rt overnight. Themixture was partitioned between water and dichloromethane, and theorganic layer was separated and dried over sodium sulfate. The dryingagent was filtered off, and the solution was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel using asolvent gradient of 1-10% methanol in dichloromethane to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (d, J=2.3 Hz, 1H), 7.73 (d,J=8.1 Hz, 1H), 7.34 (dd, J=8.6, 7.2 Hz, 2H), 7.23-7.11 (m, 3H), 6.59 (s,1H), 6.04 (dd, J=13.0, 10.1 Hz, 1H), 5.63 (dd, J=8.2, 2.2 Hz, 1H), 5.50(s, 1H), 4.83 (hept, J=6.2 Hz, 1H), 4.37-4.21 (m, 3H), 3.84-3.70 (m,1H), 2.54 (s, 2H), 1.22 (d, J=3.8 Hz, 6H), 1.20 (d, J=7.1 Hz, 3H), 1.12(dd, J=6.2, 1.8 Hz, 6H).

Example 36. Ethyl1-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)cyclopropane-1-carboxylate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (501 MHz, DMSO-d₆) δ 11.58 (s, 1H), 7.70-7.57 (m,1H), 7.41-7.32 (m, 2H), 7.21-7.14 (m, 3H), 7.02 (s, 1H), 6.65-6.51 (m,2H), 5.55 (dd, J=8.1, 2.2 Hz, 1H), 4.44-4.27 (m, 2H), 4.13-3.95 (m, 4H),1.30-1.23 (m, 2H), 1.13-1.08 (m, 3H), 1.07-0.91 (m, 2H).

Example 37. Isopropyl1-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)cyclopropane-1-carboxylate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.62-11.57 (m, 1H),7.68-7.55 (m, 1H), 7.41-7.31 (m, 2H), 7.23-7.13 (m, 3H), 7.11-6.94 (m,1H), 6.67-6.58 (m, 11H), 6.53 (d, J=15.7 Hz, 1H), 5.55 (dd, J=8.2, 2.2Hz, 1H), 4.81 (hept, J==6.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.14-3.94 (m,2H), 1.29-1.20 (m, 2H), 1.14-1.07 (m, 6H), 1.07-0.87 (m, 2H).

Example 38. Ethyl2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-methoxy-2-methylpropanoate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (500 MHz, DMSO-d₆) δ 11.61 (d, J=2.6 Hz, 1H),7.73-7.61 (n, 1H), 7.43-7.35 (m, 2H), 7.27-7.16 (m, 3H), 7.11-7.00 (m,1H), 6.70-6.63 (m, 1H), 5.84-5.71 (m, 1H), 5.59-5.52 (m, 1H), 4.45-4.27(m, 2H), 4.18-3.99 (m, 4H), 3.24-3.19 (m, 3H), 1.43-1.31 (m, 3H),1.19-1.11 (m, 3H).

Example 39. EthylN-((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-O-methyl-L-threoninate

The title compound was prepared using a method similar to that describedfor Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (d, J=2.2 Hz, 1H), 7.62(d, J=8.2 Hz, 1H), 7.36-7.29 (m, 2H). 7.22-7.16 (m, 2H), 7.17-7.10 (m,1H), 7.01-6.92 (m, 1H), 6.60 (s, 1H), 5.81 (t, J=11.3 Hz, 1H), 5.54 (dd,J=8.1, 2.2 Hz, 1H), 4.84 (hept, J=6.3 Hz, 1H), 4.40-4.22 (m, 2H),4.12-3.94 (m, 2H), 3.82-3.71 (m, 1H), 3.67-3.57 (m, 1H), 3.17 (s, 3H),1.11 (dd, J=6.2, 4.7 Hz, 6H), 1.05 (d, J=6.2 Hz, 3H).

Example 40. ethyl2-(((R)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The title compound was prepared using a method similar to that describedfor Example 5, substituting the product from Example 3E for the productfrom Example 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 11.64 (s, 0H), 7.51 (d,J=8.2 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.24-7.14 (m, 3H), 6.73 (d, J=6.8Hz, 1H), 6.24 (d, J=17.6 Hz, 1H), 6.00 (d, J=9.6 Hz, 1H), 5.60 (d, J=8.1Hz, 1H), 4.42-4.22 (m, 4H), 4.09-3.99 (m, 3H), 1.38 (s, 3H), 1.33 (s,3H), 1.14 (t, J=7.1 Hz, 3H).

Example 41. ethyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The title compound was prepared using a method similar to that describedfor Example 5, substituting the product from Example 3E for the productfrom Example 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 11.39 (s, 1H), 7.56 (d,J=8.1 Hz, 1H), 7.39-7.32 (m, 2H), 7.23-7.13 (m, 2H), 6.66 (s, 1H), 6.22(d, J=17.7 Hz, 1H), 5.92 (d, J=9.6 Hz, 1H), 5.58 (d, J=8.1 Hz, 1H),4.41-4.22 (m, 3H), 4.02 (q, J=7.1 Hz, 3H), 1.37 (s, 3H), 1.33 (s, 3H),1.12 (t, J=7.1 Hz, 3H).

When tested, the compound of Example 41 showed similar anti-HCV potencyas sofosbuvir, and provided a 6-fold higher liver triphosphate levelsthan sofosbuvir in a single-dose dog liver biopsy study. On repeatdosing (4 days QD), the liver triphosphate levels were comparable tosofosbuvir when given at a five-fold lower dose than sofosbuvir.

Example 42. ethyl2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The title compound was obtained as a 2.5:1 mixture of phosphoramidateisomers: ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 7.61-7.44 (m, 1H),7.38-7.29 (m, 2H), 7.22-7.10 (m, 3H), 6.08-5.77 (m, 3H), 5.52-5.44 (m,1H), 4.35 (dd, J=11.3, 6.1 Hz, 1H), 4.29-4.18 (m, 1H), 4.04-3.94 (m,3H), 3.91-3.64 (m, 1H), 1.40-1.28 (m, 6H), 1.28-1.14 (m, 3H), 1.13-1.06(m, 3H); MS (ESI) m/z @530.1 (M+H).

In human hepatocyte wash-out experiments (cells incubated for 4 hourswith 100 μM of a compound of interest and then the active triphosphatewas measured at 24 hours), the compound of Example 42 showed asignificantly higher intracellular triphosphate concentration thansofosbuvir.

Example 43. ethyl2-(((((2R,3R,4R,5R)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The title compound was obtained as a 2.5:1 mixture of phosphoramidateisomers: ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 7.70-7.52 (m, 1H),7.41-7.30 (m, 2H), 7.24-7.09 (m, 3H), 6.24 (s, 1H), 6.18-6.08 (m, 1H),6.00-5.86 (m, 1H), 5.49-5.39 (m, 1H), 4.44-4.22 (m, 2H), 4.10-3.77 (m,4H), 1.41 (s, 3H), 1.36 (s, 3H), 1.31 (d, J=3.3 Hz, 3H), 1.13-1.07 (m,3H); MS (ESI) m/z @ 546.1 (M+H).

In human hepatocyte wash-out experiments (cells incubated for 4 hourswith 100 μM of a compound of interest and then the active triphosphatewas measured at 24 hours), the compound of Example 43 showed acomparable or higher intracellular triphosphate concentration thansofosbuvir.

Example 44. ethyl2-(((((2R,3R,5R)-4,4-dichloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

The title compound was obtained as a 2.2:1 mixture of phosphoramidateisomers: ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 7.67-7.55 (m, 1H),7.39-7.30 (m, 2H), 7.23-7.05 (m, 3H), 7.05-6.93 (m, 1H), 6.43-6.37 (m,1H), 6.03-5.93 (m, 1H), 5.55-5.48 (m, 1H), 4.42-4.21 (m, 3H), 4.07-3.92(m, 3H), 1.40-1.26 (m, 6H), 1.16-1.06 (m, 3H); MS (ESI) m/z @ 566.1(M+H).

In human hepatocyte wash-out experiments (cells incubated for 4 hourswith 100 μM of a compound of interest and then the active triphosphatewas measured at 24 hours), the compound of Example 44 showed anintracellular triphosphate concentration comparable to sofosbuvir.

Example 45. ethyl2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

Example 45a. ethyl2-((((6-cyanopyridin-3-yl)oxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

To a solution of phenol (225 mg, 2.386 mmol) in anhydrousdichloromethane (20 ml) at −78° C. under a dry, inert atmosphere (N₂),was added phosphoryl trichloride (0.222 ml, 2.386 mmol)) in one portion.The resulting solution was stirred while triethylamine (1.00 ml, 7.17mmol)) was added dropwise over 10 min. The resulting mixture was stirredat −78 C for 1 hr, and then was allowed to warm to an internaltemperature of 0° C. and stirred for 30 min. The stirred mixture wasthen cooled to −78° C., and a solution of ethyl2-amino-2-methylpropanoate hydrochloride (400 mg, 2.386 mmol)) inanhydrous dichloromethane (20 ml) was added dropwise over 20 min. Theresulting mixture was stirred at −78 for 1 hr, and was then allowed towarm to an internal temperature of 0° C. To the stirred mixture at 0° C.was added a solution of 5-hydroxypicolinonitrile (287 mg, 2.386 mmol)and triethylamine (0.333 ml, 2.386 mmol)) in anhydrous dichloromethane(10 ml) slowly by dropwise addition. When the addition was complete, thesuspension was allowed to warm to room temperature and stirred for 16hr. The reaction mixture was washed with aqueous 1 M NaHSO₄ (30 mL). Thelayers were separated and the organic layer was dried over sodiumsulfate. The drying agent was filtered off, and the filtrated wasconcentrated in vacuo to give a crude product that was purified bycolumn chromatography on silica gel using a solvent gradient of 0-30%ethyl acetate in heptanes. The title compound was obtained as acolorless solid (208 mg, 22%).

Example 45b. ethyl2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

A solution of the product from Example 1H (58 mg, 0.170 mmol) inanhydrous THF (1.5 ml), and DMPU (0.1 ml) was cooled to 0° C. A 1.0 Msolution of tert-butylmagnesium chloride in THF (0.187 ml, 0.187 mmol)was added dropwise, and the resulting mixture was stirred for 30 minbefore the product from Example 45a (132 mg, 0.340 mmol) was added inone portion. The reaction mixture was allowed to warm to roomtemperature and stirred for 12 hrs. The reaction was quenched with asaturated solution of NH₄Cl, and the mixture was extracted withdichloromethane (2×). The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo, and the product wasisolated by C18 HPLC using a solvent gradient of 5-95% acetonitrile inwater (0.1% TFA). The title compound was obtained as a colorless solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.57 (d, J=2.3 Hz, 1H), 7.70-7.54 (m, 1H),7.40-7.32 (m, 2H), 7.23-7.12 (m, 3H), 7.01 (s, 1H), 6.63 (s, 1H),6.03-5.91 (m, 1H), 5.57-5.48 (m, 1H), 4.42-4.25 (m, 2H), 4.13-3.97 (m,4H), 1.40-1.30 (m, 6H), 1.15-1.09 (m, 3H).

Example 46. (S)-isopropyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Example 46A.(4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)dihydrofuran-2(3H)-one

To a solution of the product from Example 1A (1.95 kg, 14.7 mol),N,N-dimethylaminopyridine (90.1 g, 738 mmol) and imidazole (3.52 kg,51.6 mol) in N,N-dimethylformamide (15.0 L) at 15° C. was addedtert-butyldimethylsilyl chloride (5.34 kg, 35.4 mol) over ca. 45 min,and the mixture was stirred 12 hours. TLC (Petroleum ether:Ethylacetate=20:1, R_(f)=0.40) indicated the starting material was consumedcompletely and one new spot formed. The reaction mixture was dilutedwith H₂O (60 L) and extracted with methyl tert-butyl ether (10 L×3). Thecombined organic layers were washed with brine (3 L), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography on silica gel, elutingwith a solvent gradient of 2-5% ethyl acetate in petroleum ether to givethe title compound as a colorless solid (3.25 kg, 61% yield); ¹H NMR(400 MHz, CDCl₃) □□4.49 (dt, J=6.4, 2.0 Hz, 1H), 4.30-4.32 (m, 1H),3.71-3.82 (m, 2H), 2.77-2.83 (m, 1H), 2.34-2.43 (m, 1H), 0.82-0.92 (m,18H), 0.03-0.09 (m, 12H).

Example 46B.(4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-chlorodihydrofuran-2(3H)-one

To a solution of the product from Example 46B (300 g, 831 mmol) andN-chlorosuccinimide (233 g, 1.75 mol) in tetrahydrofuran (2.0 L) at −65°C. was added a solution of lithium bis-trimethylsilylamide intetrahydrofuran (1 M, 2.16 L) drop-wise over ca. 45 min. The mixture wasstirred at −70° C. for 0.5 hours and then quenched with acetic acid (630g, 10.5 mol). The mixture was warmed to 0° C. and Zn (81.5 g, 1.25 mol)was added in portions. The mixture was stirred at 20° C. for 12 hours.The reaction mixture was filtered with celite, and the filter cake waswashed with methyl tert-butyl ether (1 L×3) and water (1 L×3). Themixture was diluted with water (15 L) and then the mixture was extractedwith methyl tert-butyl ether (4000 mL×3). The combined organic layerswere washed with brine (4 L), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue wasdissolved with n-hexane (10 L) and cooled to −60° C. to give a colorlesssolid that was collected by filtration and dried to give the titlecompound as a colorless solid.

Example 46C.(3S,4R,5R)-3-bromo-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-chlorodihydrofuran-2(3H)-one

To a solution of the product from Example 46B (50 g, 126 mmol) and1,2-dibromo-1,1,2,2-tetrachloro-ethane (65 g, 202 mmol) intetrahydrofuran (500 mL) −90° C. was added a solution of potassiumbis-trimethylsilylamide in tetrahydrofuran (1 M, 269 mL) drop-wise overca. 1.5 hours. The resulting mixture was stirred for 0.5 hours at −90°C. Methanol (40 mL) was added drop-wise at −90° C., and the mixture wasextracted with methyl tert-butyl ether (200 mL×3). The combined organiclayers were washed with brine (500 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with a solvent gradient of 1-3%ethyl acetate in petroleum ether to give a crude compound, which wasfurther purified by recrystallization from n-hexane (60 mL) at −60° C.to give the title compound as a colorless solid (18 g); ¹H NMR (400 MHz,CDCl₃) □□ 4.83 (d, J=7.2 Hz, 1H), 4.12 (d, J=7.2 Hz, 1H), 3.94 (d,J=12.4 Hz, 1H), 3.72 (d, J=12.4 Hz, 1H), 0.89 (s, 9H), 0.81 (s, 9H),0.21 (s, 3H), 0.11 (s, 3H), 0.04 (s, 6H).

Example 46D.(3S,4R,5R)-3-bromo-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-chlorotetrahydrofuran-2-ol

To a solution of the product from Example 46C (1.0 g, 1.792 mmol) inanhydrous toluene (10 ml) at −78° C. was added diisobutylaluminumhydride (1.0 M in toluene, 2.15 ml, 2.15 mmol) dropwise over 5 minutes.The resulting mixture was stirred at −78° C. for 90 minutes. Methanol(0.5 ml) was added and the mixture was allowed to stir and slowly warmto room temperature. Aqueous 1 N HCl (10 ml) and ethyl acetate (10 ml)were added, and the mixture was stirred at room temperature for 30minutes. The layers were separated, and the aqueous layer was washedwith ethyl acetate (10 ml). The combined organic layers were dried overNa₂SO₄, and then filtered and concentrated in vacuo to give a colorlessoil that slowly crystallized under vacuum. The title compound wasobtained as a colorless solid (1.0 g, 100%).

Example 46E.(3S,4R,5R)-3-bromo-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-chlorotetrahydrofuran-2-yl4-methoxybenzoate

To a solution of the product from Example 46D (1.0 g, 1.79 mmol) andtriethylamine (0.25 ml, 1.79 mmol) in anhydrous dichloromethane (12 ml)at 0° C. was added 4-methoxybenzoyl chloride (0.335 g, 1.964 mmol) andthe mixture was stirred at 0° C. for 10 minutes. 4-Dimethylaminopyridine(0.022 g, 0.179 mmol) was added, and the mixture was allowed to warm toroom temperature and stirred for 90 minutes. The reaction mixture waspartitioned between water and dichloromethane (3×), and the combinedorganic layers dried over Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by column chromatography on silica gelusing a solvent gradient of 0-20% ethyl acetate in heptanes. The titlecompound was obtained a colorless oil (1.17 g, 94%).

Example 46F.(3S,4R,5R)-3-bromo-3-chloro-5-(((4-methoxybenzoyl)oxy)methyl)tetrahydrofuran-2,4-diylbis(4-methoxybenzoate)

To a solution of the product from Example 46E (1.17 g, 1.685 mmol) andacetic acid (0.193 ml, 3.37 mmol) in tetrahydrofuran (17 ml) at 0° C.was added tetra-N-butylammonium fluoride (1.0M in THF, 3.71 ml, 3.71mmol) and the mixture was stirred at 0° C. for 3 hours. The mixture wasallowed to warm to room temperature and stirred for 30 minutes, and wasthen partitioned between water and ethyl acetate (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. The residue was dissolved in anhydrous dichloromethane (17 ml),and 4-methoxybenzoyl chloride (0.719 g, 4.21 mmol), triethylamine (0.705ml, 5.06 mmol), and 4-dimethylaminopyridine (0.021 g, 0.169 mmol) wereadded. The resulting mixture was stirred at room temperature overnight,and was then partitioned between water and dichloromethane. The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo, and thecrude product was purified on silica gel using a solvent gradient of0-20% ethyl acetate in heptanes. The title compound was obtained as acolorless solid (0.46 g, 42%).

Example 46G.(2R,3R,4S)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-4-bromo-4-chloro-2-(((4-methoxybenzoyl)oxy)methyl)tetrahydrofuran-3-yl4-methoxybenzoate

A mixture of N-benzoyl-cytosine (0.149 g, 0.692 mmol) and trimethylsilylN-(trimethylsilyl)acetimidate (0.203 ml, 0.830 mmol) in anhydrouschlorobenzene (1.0 ml) was stirred at 80° C. under a dry N₂ atmospherefor 90 minutes. The resulting solution was cooled to room temperature,and a solution of the product from Example 46F (0.15 g, 0.231 mmol) inchlorobenzene (1.0 ml) was added, followed by tin tetrachloride (0.163ml, 1.385 mmol). The resulting mixture was stirred at 80° C. under a dryN₂ atmosphere for 16 hours. The cooled mixture was diluted with ethylacetate (3 ml), and washed with saturated aqueous sodium bicarbonate (3ml). The layers were separated, and the aqueous layer was washed withethyl acetate (2×3 ml). The combined org layers were dried over Na₂SO₄,filtered and concentrated in vacuo to give a crude product that waspurified by column chromatography on silica gel using a solvent gradientof 0-60% ethyl acetate in heptanes to give the title compound (96 mg,58%).

Example 46H.1-((2R,3S,4R,5R)-3-bromo-3-chloro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione

A solution of the product from Example 46G (95 mg, 0.133 mmol) in aceticacid (1.2 ml) and water (0.3 ml) was stirred at 110° C. for 4 hours. Themixture was concentrated in vacuo, and the residue was dissolved inammonia (7 M in methanol, 1.0 ml, 7.00 mmol) and stirred at roomtemperature for 3 days. The mixture was concentrated in vacuo, and thecrude product was purified by column chromatography on silica gel usinga solvent gradient of 0-5% methanol in dichloromethane. The anomericmixture of products eluted at 5% methanol as an overlapping pair ofpeaks, with the desired beta anomer eluting first. Mixed fractions wererepurified using the same conditions. The title compound was obtained asa colorless solid (13 mg, 29%).

Example 461. (S)-isopropyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

The product of Example 46H (12 mg, 0.035 mmol) was reacted with thecorresponding phosphoramidate prodrug moiety compound. The crude productwas purified by column chromatography on silica gel eluting with asolvent gradient of 0-5% methanol in dichloromethane to give the titlecompound (7.5 mg, 35%); ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.60(d, J=8.1 Hz, 1H), 7.34 (dd, J=8.6, 7.2 Hz, 2H), 7.24-7.10 (m, 3H), 6.89(d, J=6.0 Hz, 1H), 6.38 (s, 1H), 6.06 (dd, J=13.0, 10.1 Hz, 1H), 5.55(d, J=8.2 Hz, 1H), 4.82 (hept, J=6.3 Hz, 1H), 4.48-4.40 (m, 1H),4.39-4.21 (m, 2H), 4.01-3.94 (m, 1H), 3.85-3.70 (m, 1H), 1.20 (d, J=7.0Hz, 3H), 1.12 (d, J=6.2 Hz, 6H); MS (ESI+) m/z 611.9 (M+H)⁺.

The foregoing description of the present invention provides illustrationand description, but is not intended to be exhaustive or to limit theinvention to the precise one disclosed. Modifications and variations arepossible in light of the above teachings or may be acquired frompractice of the invention. Thus, it is noted that the scope of theinvention is defined by the claims and their equivalents.

What is claimed is:
 1. A compound of Formula VII″, or a pharmaceuticallyacceptable salt thereof

wherein, X is selected from the group consisting of O and C═CH₂; R₁ andR₂ are independently selected from the group consisting of F, Cl, Br,CH₃, CHF₂ and CCH, R₃, R₄ and R₅ are independently selected from thegroup consisting of H, D, F, N₃, OCH₃, CN, OH, 1H-tetrazol-5-yl,2H-tetrazol-2-yl, 1H-tetrazol-1-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yland 1H-imidazol-5-yl; and P₁ is selected from a group consisting of:


2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R₁ is Br and R₂ is F or R₁ is Cl and R₂ is F.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R₁ is Br and R₂ is F.
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R₃ is OH and R₄ is H.5. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R₃ is OH.
 6. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein X is O.
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R₅ is selected from a group consisting of H, D, F, N₃, OCH₃, CN,OH, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl,1H-imidazol-1-yl, 1H-imidazol-2-yl and 1H-imidazol-5-yl.
 8. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein saidcompound is selected from a group consisting of: (S)-isopropyl2-(((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, (S)-isopropyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoateethyl2-(((R)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate,ethyl2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate,ethyl2-(((((2R,3R,4R,5R)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate,ethyl2-(((((2R,3R,5R)-4,4-dichloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate,and (S)-isopropyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate.
 9. The compound of claim 1, where said compound is(S)-isopropyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate,or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, where said compound is Ethyl2-(((((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate,or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1, where said compound is Ethyl2-(((R)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate,or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, where said compound is Ethyl2-(((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate,or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, where said compound is Ethyl2-(((S)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate,or a pharmaceutically acceptable salt thereof.
 14. A method for treatingHCV, comprising administering a compound or salt of claim 1 to a patientinfected with Hepatitis C Virus.
 15. A method for treating HCV,comprising administering a compound or salt of claim 7 to a patientinfected with Hepatitis C Virus.
 16. A pharmaceutical compositioncomprising a compound or salt of claim
 1. 17. A pharmaceuticalcomposition comprising a compound or salt of claim 8.